C10 carbamoyloxy substituted taxanes

ABSTRACT

Taxanes having a carbamoyloxy substituent at C(10), a hydroxy substituent at C(7), and a range of C(2), C(9), C(14), and side chain substituents.

REFERENCE TO RELATED APPLICATION

[0001] This application claims priority from U.S. provisionalapplication Serial No. 60/179,793, filed on Feb. 2, 2000.

BACKGROUND OF THE INVENTION

[0002] The present invention is directed to novel taxanes which haveexceptional utility as antitumor agents.

[0003] The taxane family of terpenes, of which baccatin III and taxolare members, has been the subject of considerable interest in both thebiological and chemical arts. Taxol itself is employed as a cancerchemotherapeutic agent and possesses a broad range of tumor-inhibitingactivity. Taxol has a 2′R, 3′S configuration and the followingstructural formula:

[0004] wherein Ac is acetyl.

[0005] Colin et al. reported in U.S. Pat. No. 4,814,470 that certaintaxol analogs have an activity significantly greater than that of taxol.One of these analogs, commonly referred to as docetaxel, has thefollowing structural formula:

[0006] Although taxol and docetaxel are useful chemotherapeutic agents,there are limitations on their effectiveness, including limited efficacyagainst certain types of cancers and toxicity to subjects whenadministered at various doses. Accordingly, a need remains foradditional chemotherapeutic agents with improved efficacy and lesstoxicity.

SUMMARY OF THE INVENTION

[0007] Among the objects of the present invention, therefore, is theprovision of taxanes which compare favorably to taxol and docetaxel withrespect to efficacy as anti-tumor agents and with respect to toxicity.In general, these taxanes possess a carbamoyloxy substituent at C-10, ahydroxy substituent at C-7 and a range of C-3′ substituents.

[0008] Briefly, therefore, the present invention is directed to thetaxane composition, per se, to pharmaceutical compositions comprisingthe taxane and a pharmaceutically acceptable carrier, and to methods ofadministration.

[0009] Other objects and features of this invention will be in partapparent and in part pointed out hereinafter.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0010] In one embodiment of the present invention, the taxanes of thepresent invention correspond to structure (1):

[0011] wherein

[0012] R₂ is acyloxy;

[0013] R₇ is hydroxy;

[0014] R₉ is keto, hydroxy, or acyloxy;

[0015] R₁₀ is carbamoyloxy;

[0016] R₁₄ is hydrido or hydroxy;

[0017] X₃ is substituted or unsubstituted alkyl, alkenyl, alkynyl,phenyl or heterocyclo;

[0018] X₅ is —COX₁₀, —COOX₁₀, or —CONHX₁₀;

[0019] X₁₀ is hydrocarbyl, substituted hydrocarbyl, or heterocyclo;

[0020] Ac is acetyl; and

[0021] R₇, R₉, and R₁₀ independently have the alpha or betastereochemical configuration.

[0022] In one embodiment, R₂ is an ester (R_(2a)C(O)O—), a carbamate(R_(2a)R_(2b)NC(O)O—), a carbonate (R_(2a)OC(O)O—), or a thiocarbamate(R_(2a)SC(O)O—) wherein R_(2a) and R_(2b) are independently hydrogen,hydrocarbyl, substituted hydrocarbyl or heterocyclo. In a preferredembodiment, R₂ is an ester (R_(2a)C(O)O—), wherein R_(2a) is aryl orheteroaromatic. In another preferred embodiment, R₂ is an ester(R_(2a)C(O)O—), wherein R_(2a) is substituted or unsubstituted phenyl,furyl, thienyl, or pyridyl. In one particularly preferred embodiment, R₂is benzoyloxy.

[0023] While R₉ is keto in one embodiment of the present invention, inother embodiments R₉ may have the alpha or beta stereochemicalconfiguration, preferably the beta stereochemical configuration, and maybe, for example, α- or β-hydroxy or α- or β-acyloxy. For example, whenR₉ is acyloxy, it may be an ester (R_(9a)C(O)O—), a carbamate(R_(9a)R_(9b)NC(O)O—), a carbonate (R_(9a)OC(O)O—), or a thiocarbamate(R_(9a)SC(O)O—) wherein R_(9a) and R_(9b) are independently hydrogen,hydrocarbyl, substituted hydrocarbyl or heterocyclo. If R₉ is an ester(R_(9a)C(O)O—), R_(9a) is subsituted or unsubstituted alkyl, subsitutedor unsubstituted alkenyl, subsituted or unsubstituted aryl or subsitutedor unsubstituted heteroaromatic. Still more preferably, R₉ is an ester(R_(9a)C(O)O—), wherein R_(9a) is substituted or unsubstituted phenyl,subsituted or unsubstituted furyl, subsituted or unsubstituted thienyl,or substituted or unsubstituted pyridyl. In one embodiment R₉ is(R_(9a)C(O)O—) wherein R_(9a) is methyl, ethyl, propyl (straight,branched or cyclic), butyl (straight, branched or cyclic), pentyl,(straight, branched or cyclic), or hexyl (straight, branched or cyclic).In another embodiment R₉ is (R_(9a)C(O)O—) wherein R_(9a) is substitutedmethyl, substituted ethyl, substituted propyl (straight, branched orcyclic), substituted butyl (straight, branched or cyclic), substitutedpentyl, (straight, branched or cyclic), or substituted hexyl (straight,branched or cyclic) wherein the substituent(s) is/are selected from thegroup consisting of heterocyclo, alkoxy, alkenoxy, alkynoxy, aryloxy,hydroxy, protected hydroxy, keto, acyloxy, nitro, amino, amido, thiol,ketal, acetal, ester and ether moieties, but not phosphorous containingmoieties.

[0024] In one embodiment, R₁₀ is R_(10a)R_(10b)NCOO— wherein R_(10a) andR_(10b) are independently hydrogen, hydrocarbyl, substitutedhydrocarbyl, or heterocyclo. Exemplary preferred R₁₀ substituentsinclude R_(10a)R_(10b)NCOO— wherein (a) R_(10a) and R_(10b) are eachhydrogen, (b) one of R_(10a) and R_(10b) is hydrogen and the other is(i) substituted or unsubstituted C₁ to C₈ alkyl such as methyl, ethyl,or straight, branched or cyclic propyl, butyl, pentyl, or hexyl; (ii)substituted or unsubstituted C₂ to C₈ alkenyl such as ethenyl orstraight, branched or cyclic propenyl, butenyl, pentenyl or hexenyl;(iii) substituted or unsubstituted C₂ to C₈ alkynyl such as ethynyl orstraight or branched propynyl, butynyl, pentynyl, or hexynyl; (iv)substituted or unsubstituted phenyl, or (v) substituted or unsubstitutedheteroaromatic such as furyl, thienyl, or pyridyl, or (c) R_(10a) andR_(10b) are independently (i) substituted or unsubstituted C₁ to C₈alkyl such as methyl, ethyl, or straight, branched or cyclic propyl,butyl, pentyl, or hexyl; (ii) substituted or unsubstituted C₂ to C₈alkenyl such as ethenyl or straight, branched or cyclic propenyl,butenyl, pentenyl or hexenyl; (iii) substituted or unsubstituted C₂ toC₈ alkynyl such as ethynyl or straight or branched propynyl, butynyl,pentynyl, or hexynyl; (iv) substituted or unsubstituted phenyl, or (v)substituted or unsubstituted heteroaromatic such as furyl, thienyl, orpyridyl. The substituents may be those identified elsewhere herein forsubstituted hydrocarbyl. In one embodiment, preferred R₁₀ substituentsinclude R_(10a)R_(10b)NCOO— wherein one of R_(10a) and R_(10b) ishydrogen and the other is methyl, ethyl, or straight, branched or cyclicpropyl.

[0025] Exemplary X₃ substituents include substituted or unsubstituted C₂to C₈ alkyl, substituted or unsubstituted C₂ to C₈ alkenyl, substitutedor unsubstituted C₂ to C₈ alkynyl, substituted or unsubstitutedheteroaromatics containing 5 or 6 ring atoms, and substituted orunsubstituted phenyl. Exemplary preferred X₃ substituents includesubstituted or unsubstituted ethyl, propyl, butyl, cyclopropyl,cyclobutyl, cyclohexyl, isobutenyl, furyl, thienyl, and pyridyl.

[0026] Exemplary X₅ substituents include —COX₁₀, —COOX₁₀ or —CONHX₁₀wherein X₁₀ is substituted or unsubstituted alkyl, alkenyl, phenyl orheteroaromatic. Exemplary preferred X₅ substituents include —COX₁₀,—COOX₁₀ or —CONHX₁₀ wherein X₁₀ is (i) substituted or unsubstituted C₁to C₈ alkyl such as substituted or unsubstituted methyl, ethyl, propyl(straight, branched or cyclic), butyl (straight, branched or cyclic),pentyl (straight, branched or cyclic), or hexyl (straight, branched orcyclic); (ii) substituted or unsubstituted C₂ to C₈ alkenyl such assubstituted or unsubstituted ethenyl, propenyl (straight, branched orcyclic), butenyl (straight, branched or cyclic), pentenyl (straight,branched or cyclic) or hexenyl (straight, branched or cyclic); (iii)substituted or unsubstituted C₂ to C₈ alkynyl such as substituted orunsubstituted ethynyl, propynyl (straight or branched), butynyl(straight or branched), pentynyl (straight or branched), or hexynyl(straight or branched); (iv) substituted or unsubstituted phenyl, or (v)substituted or unsubstituted heteroaromatic such as furyl, thienyl, orpyridyl, wherein the substituent(s) is/are selected from the groupconsisting of heterocyclo, alkoxy, alkenoxy, alkynoxy, aryloxy, hydroxy,protected hydroxy, keto, acyloxy, nitro, amino, amido, thiol, ketal,acetal, ester and ether moieties, but not phosphorous containingmoieties.

[0027] In one embodiment of the present invention, the taxanes of thepresent invention correspond to structure (2):

[0028] wherein

[0029] R₇ is hydroxy;

[0030] R₁₀ is carbamoyloxy;

[0031] X₃ is substituted or unsubstituted alkyl, alkenyl, alkynyl, orheterocyclo, wherein alkyl comprises at least two carbon atoms;

[0032] X₅ is —COX₁₀, —COOX₁₀, or —CONHX₁₀; and

[0033] X₁₀ is hydrocarbyl, substituted hydrocarbyl, or heterocyclo.

[0034] For example, in this preferred embodiment in which the taxanecorresponds to structure (2), R₁₀ may be R_(10a)R_(10b)NCOO— wherein oneof R_(10a) and R_(10b) is hydrogen and the other is (i) substituted orunsubstituted C₁ to C₈ alkyl such as methyl, ethyl, or straight,branched or cyclic propyl, butyl, pentyl, or hexyl; (ii) substituted orunsubstituted C₂ to C₈ alkenyl such as ethenyl or straight, branched orcyclic propenyl, butenyl, pentenyl or hexenyl; (iii) substituted orunsubstituted C₂ to C₈ alkynyl such as ethynyl or straight or branchedpropynyl, butynyl, pentynyl, or hexynyl; (iv) phenyl or substitutedphenyl such as nitro, alkoxy or halosubstituted phenyl, or (v)substituted or unsubstituted heteroaromatic such as furyl, thienyl, orpyridyl. The substituents may be those identified elsewhere herein forsubstituted hydrocarbyl. In one embodiment, preferred R₁₀ substituentsinclude R_(10a)R_(10b)NCOO— wherein one of R_(10a) and R_(10b) ishydrogen and the other is substituted or unsubstituted, preferablyunsubstituted methyl, ethyl, or straight, branched or cyclic propyl. Inanother embodiment, preferred R₁₀ substituents includeR_(10a)R_(10b)NCOO— wherein one of R_(10a) and R_(10b) is hydrogen andthe other is substituted or unsubstituted phenyl or heterocyclo. WhileR_(10a) and R_(10b) are selected from among these, in one embodiment X₃is selected from substituted or unsubstituted alkyl, alkenyl, phenyl orheterocyclo, more preferably substituted or unsubstituted alkenyl,phenyl or heterocyclo, still more preferably substituted orunsubstituted phenyl or heterocyclo, and still more preferablyheterocyclo such as furyl, thienyl or pyridyl. While R_(10a,) R_(10b),and X₃ are selected from among these, in one embodiment X₅ is selectedfrom —COX₁₀ wherein X₁₀ is phenyl, alkyl or heterocyclo, more preferablyphenyl. Alternatively, while R₁₀a, R_(10b), and X₃ are selected fromamong these, in one embodiment X₅ is selected from —COX₁₀ wherein X₁₀ isphenyl, alkyl or heterocyclo, more preferably phenyl, or X₅ is —COOX₁₀wherein X₁₀ is alkyl, preferably t-butyl. Among the more preferredembodiments, therefore, are taxanes corresponding to structure 2 inwhich (i) X₅ is —COOX₁₀ wherein X₁₀ is tert-butyl or X₅ is —COX₁₀wherein X₁₀ is phenyl, (ii) X₃ is substituted or unsubstitutedcycloalkyl, alkenyl, phenyl or heterocyclo, more preferably substitutedor unsubstituted isobutenyl, phenyl, furyl, thienyl, or pyridyl, stillmore preferably unsubstituted isobutenyl, furyl, thienyl or pyridyl, and(iii) R₁₀ is R_(10a)R_(10b)NCOO—, one of R_(10a) and R_(10b) is hydrogenand the other is substituted or unsubstituted substituted orunsubstituted C₁ to C₈ alkyl, phenyl or heterocyclo.

[0035] Among the preferred embodiments, therefore, are taxanescorresponding to structure 1 or 2 wherein R₁₀ is R_(10a)R_(10b)NCOO—wherein R_(10a) is methyl and R_(10b) is hydrido. In this embodiment, X₃is preferably cycloalkyl, isobutenyl, phenyl, substituted phenyl such asp-nitrophenyl, or heterocyclo, more preferably heterocyclo, still morepreferably furyl, thienyl or pyridyl; and X₅ is preferably benzoyl,alkoxycarbonyl, or heterocyclocarbonyl, more preferably benzoyl,t-butoxycarbonyl or t-amyloxycarbonyl. In one alternative of thisembodiment, X₃ is heterocyclo; X₅ is benzoyl, alkoxycarbonyl, orheterocyclocarbonyl, more preferably benzoyl, t-butoxycarbonyl ort-amyloxycarbonyl, still more preferably t-butoxycarbonyl; R₂ isbenzoyl, R₉ is keto and R₁₄ is hydrido. In another alternative of thisembodiment, X₃ is heterocyclo; X₅ is benzoyl, alkoxycarbonyl, orheterocyclocarbonyl, more preferably benzoyl, t-butoxycarbonyl ort-amyloxycarbonyl, still more preferably t-butoxycarbonyl; R₂ isbenzoyl, R₉ is keto and R₁₄ is hydrido. In another alternative of thisembodiment, X₃ is heterocyclo; X₅ is benzoyl, alkoxycarbonyl, orheterocyclocarbonyl, more preferably benzoyl, t-butoxycarbonyl ort-amyloxycarbonyl, still more preferably t-butoxycarbonyl; R₂ isbenzoyl, R₉ is keto and R₁₄ is hydroxy. In another alternative of thisembodiment, X₃ is heterocyclo; X₅ is benzoyl, alkoxycarbonyl, orheterocyclocarbonyl, more preferably benzoyl, t-butoxycarbonyl ort-amyloxycarbonyl, still more preferably t-butoxycarbonyl; R₂ isbenzoyl, R₉ is hydroxy and R₁₄ is hydroxy. In another alternative ofthis embodiment, X₃ is heterocyclo; X₅ is benzoyl, alkoxycarbonyl, orheterocyclocarbonyl, more preferably benzoyl, t-butoxycarbonyl ort-amyloxycarbonyl, still more preferably t-butoxycarbonyl; R₂ isbenzoyl, R₉ is hydroxy and R₁₄ is hydrido. In another alternative ofthis embodiment, X₃ is heterocyclo; X₅ is benzoyl, alkoxycarbonyl, orheterocyclocarbonyl, more preferably benzoyl, t-butoxycarbonyl ort-amyloxycarbonyl, still more preferably t-butoxycarbonyl; R₂ isbenzoyl, R₉ is acyloxy and R₁₄ is hydroxy. In another alternative ofthis embodiment, X₃ is heterocyclo; X₅ is benzoyl, alkoxycarbonyl, orheterocyclocarbonyl, more preferably benzoyl, t-butoxycarbonyl ort-amyloxycarbonyl, still more preferably t-butoxycarbonyl; R₂ isbenzoyl, R₉ is acyloxy and R₁₄ is hydrido. In each of the alternativesof this embodiment when the taxane has structure 1, R₇ and R₁₀ may eachhave the beta stereochemical configuration, R₇ and R₁₀ may each have thealpha stereochemical configuration, R₇ may have the alpha stereochemicalconfiguration while R₁₀ has the beta stereochemical configuration or R₇may have the beta stereochemical configuration while R₁₀ has the alphastereochemical configuration.

[0036] Also among the preferred embodiments are taxanes corresponding tostructure 1 or 2 wherein R₁₀ is R_(10a)R_(10b)NCOO— wherein R_(10a) isethyl and R_(10b) is hydrido. In this embodiment, X₃ is preferablycycloalkyl, isobutenyl, phenyl, substituted phenyl such asp-nitrophenyl, or heterocyclo, more preferably heterocyclo, still morepreferably furyl, thienyl or pyridyl; and X₅ is preferably benzoyl,alkoxycarbonyl, or heterocyclocarbonyl, more preferably benzoyl,t-butoxycarbonyl or t-amyloxycarbonyl. In one alternative of thisembodiment, X₃ is heterocyclo; X₅ is benzoyl, alkoxycarbonyl, orheterocyclocarbonyl, more preferably benzoyl, t-butoxycarbonyl ort-amyloxycarbonyl, still more preferably t-butoxycarbonyl; R₂ isbenzoyl, R₉ is keto and R₁₄ is hydrido. In another alternative of thisembodiment, X₃ is heterocyclo; X₅ is benzoyl, alkoxycarbonyl, orheterocyclocarbonyl, more preferably benzoyl, t-butoxycarbonyl ort-amyloxycarbonyl, still more preferably t-butoxycarbonyl; R₂ isbenzoyl, R₉ is keto and R₁₄ is hydrido. In another alternative of thisembodiment, X₃ is heterocyclo; X₅ is benzoyl, alkoxycarbonyl, orheterocyclocarbonyl, more preferably benzoyl, t-butoxycarbonyl ort-amyloxycarbonyl, still more preferably t-butoxycarbonyl; R₂ isbenzoyl, R₉ is keto and R₁₄ is hydroxy. In another alternative of thisembodiment, X₃ is heterocyclo; X₅ is benzoyl, alkoxycarbonyl, orheterocyclocarbonyl, more preferably benzoyl, t-butoxycarbonyl ort-amyloxycarbonyl, still more preferably t-butoxycarbonyl; R₂ isbenzoyl, R₉ is hydroxy and R₁₄ is hydroxy. In another alternative ofthis embodiment, X₃ is heterocyclo; X₅ is benzoyl, alkoxycarbonyl, orheterocyclocarbonyl, more preferably benzoyl, t-butoxycarbonyl ort-amyloxycarbonyl, still more preferably t-butoxycarbonyl; R₂ isbenzoyl, R₉ is hydroxy and R₁₄ is hydrido. In another alternative ofthis embodiment, X₃ is heterocyclo; X₅ is benzoyl, alkoxycarbonyl, orheterocyclocarbonyl, more preferably benzoyl, t-butoxycarbonyl ort-amyloxycarbonyl, still more preferably t-butoxycarbonyl; R₂ isbenzoyl, R₉ is acyloxy and R₁₄ is hydroxy. In another alternative ofthis embodiment, X₃ is heterocyclo; X₅ is benzoyl, alkoxycarbonyl, orheterocyclocarbonyl, more preferably benzoyl, t-butoxycarbonyl ort-amyloxycarbonyl, still more preferably t-butoxycarbonyl; R₂ isbenzoyl, R₉ is acyloxy and R₁₄ is hydrido. In each of the alternativesof this embodiment when the taxane has structure 1, R₇ and R₁₀ may eachhave the beta stereochemical configuration, R₇ and R₁₀ may each have thealpha stereochemical configuration, R₇ may have the alpha stereochemicalconfiguration while R₁₀ has the beta stereochemical configuration or R₇may have the beta stereochemical configuration while R₁₀ has the alphastereochemical configuration.

[0037] Taxanes having the general formula 1 may be obtained bycarbamoylation of a suitably protected taxane intermediate having thestructural formula:

[0038] wherein X₃ and X₅ are as previously defined, P₂ is a hydroxyprotecting group, and P₇ is either hydrogen or a hydroxy protectinggroup, by reaction with an isocyanate or a carbamoyl chloride, followedby removal of the hydroxy protecting group(s).

[0039] The intermediate taxane may be obtained by treatment of aβ-lactam with an alkoxide having the taxane tetracyclic nucleus and aC-13 metallic oxide substituent to form compounds having a β-amido estersubstituent at C-13 (as described more fully in Holton U.S. Pat. No.5,466,834), followed by removal of either the C(10) protecting group, orboth the C(10) and C(7) protecting groups.

[0040] The β-lactam has the formula (3):

[0041] wherein P₂ is a hydroxy protecting group and X₃ and X₅ are aspreviously defined and the alkoxide has the formula (4):

[0042] wherein M is a metal or ammonium, and P₇ and P₁₀ are hydroxyprotecting groups.

[0043] The alkoxide may be prepared from 10-deacetylbaccatin III byprotection of the C-7 and C-10 hydroxyl groups (as described more fullyin Holton et al., PCT Patent Application WO 99/09021) followed bytreatment with a metallic amide.

[0044] Derivatives of 10-deacetylbaccatin III having alternativesubstituents at C(2), C(9) and C(14) and processes for their preparationare known in the art. Taxane derivatives having acyloxy substituentsother than benzoyloxy at C(2) may be prepared, for example, as describedin Holton et al., U.S. Pat. No. 5,728,725 or Kingston et al., U.S. Pat.No. 6,002,023. Taxanes having acyloxy or hydroxy substituents at C(9) inplace of keto may be prepared, for example as described in Holton etal., U.S. Pat. No. 6,011,056 or Gunawardana et al., U.S. Pat. No.5,352,806. Taxanes having a beta hydroxy substituent at C(14) may beprepared from naturally occurring 14-hydroxy-10-deacetylbaccatin Ill.Processes for the preparation and resolution of the β-lactam startingmaterial are generally well known. For example, the β-lactam may beprepared as described in Holton, U.S. Pat. No. 5,430,160 and theresulting enatiomeric mixtures of β-lactams may be resolved by astereoselective hydrolysis using a lipase or enzyme as described, forexample, in Patel, U.S. Pat. No. 5,879,929 Patel U.S. Pat. No. 5,567,614or a liver homogenate as described, for example, in PCT PatentApplication No. 00/41204. In a preferred embodiment in which theβ-lactam is furyl substituted at the C(4) position, the β-lactam can beprepared as illustrated in the following reaction scheme:

[0045] wherein Ac is acetyl, NEt₃ is triethylamine, CAN is cericammonium nitrate, and p-TsOH is p-toluenesulfonic acid. The beef liverresolution may be carried out, for example, by combining the enatiomericβ-lactam mixture with a beef liver suspension (prepared, for example, byadding 20 g of frozen beef liver to a blender and then adding a pH 8buffer to make a total volume of 1 L).

[0046] Compounds of formula 1 of the instant invention are useful forinhibiting tumor growth in mammals including humans and are preferablyadministered in the form of a pharmaceutical composition comprising aneffective antitumor amount of a compound of the instant invention incombination with at least one pharmaceutically or pharmacologicallyacceptable carrier. The carrier, also known in the art as an excipient,vehicle, auxiliary, adjuvant, or diluent, is any substance which ispharmaceutically inert, confers a suitable consistency or form to thecomposition, and does not diminish the therapeutic efficacy of theantitumor compounds. The carrier is “pharmaceutically orpharmacologically acceptable” if it does not produce an adverse,allergic or other untoward reaction when administered to a mammal orhuman, as appropriate.

[0047] The pharmaceutical compositions containing the antitumorcompounds of the present invention may be formulated in any conventionalmanner. Proper formulation is dependent upon the route of administrationchosen. The compositions of the invention can be formulated for anyroute of administration so long as the target tissue is available viathat route. Suitable routes of administration include, but are notlimited to, oral, parenteral (e.g., intravenous, intraarterial,subcutaneous, rectal, subcutaneous, intramuscular, intraorbital,intracapsular, intraspinal, intraperitoneal, or intrasternal), topical(nasal, transdermal, intraocular), intravesical, intrathecal, enteral,pulmonary, intralymphatic, intracavital, vaginal, transurethral,intradermal, aural, intramammary, buccal, orthotopic, intratracheal,intralesional, percutaneous, endoscopical, transmucosal, sublingual andintestinal administration.

[0048] Pharmaceutically acceptable carriers for use in the compositionsof the present invention are well known to those of ordinary skill inthe art and are selected based upon a number of factors: the particularantitumor compound used, and its concentration, stability and intendedbioavailability; the disease, disorder or condition being treated withthe composition; the subject, its age, size and general condition; andthe route of administration. Suitable carriers are readily determined byone of ordinary skill in the art (see, for example, J. G. Nairn, in:Remington's Pharmaceutical Science (A. Gennaro, ed.), Mack PublishingCo., Easton, Pa., (1985), pp. 1492-1517, the contents of which areincorporated herein by reference).

[0049] The compositions are preferably formulated as tablets,dispersible powders, pills, capsules, gelcaps, caplets, gels, liposomes,granules, solutions, suspensions, emulsions, syrups, elixirs, troches,dragees, lozenges, or any other dosage form which can be administeredorally. Techniques and compositions for making oral dosage forms usefulin the present invention are described in the following references: 7Modern Pharmaceutics, Chapters 9 and 10 (Banker & Rhodes, Editors,1979); Lieberman et al., Pharmaceutical Dosage Forms: Tablets (1981);and Ansel, Introduction to Pharmaceutical Dosage Forms 2nd Edition(1976).

[0050] The compositions of the invention for oral administrationcomprise an effective antitumor amount of a compound of the invention ina pharmaceutically acceptable carrier. Suitable carriers for soliddosage forms include sugars, starches, and other conventional substancesincluding lactose, talc, sucrose, gelatin, carboxymethylcellulose, agar,mannitol, sorbitol, calcium phosphate, calcium carbonate, sodiumcarbonate, kaolin, alginic acid, acacia, corn starch, potato starch,sodium saccharin, magnesium carbonate, tragacanth, microcrystallinecellulose, colloidal silicon dioxide, croscarmellose sodium, talc,magnesium stearate, and stearic acid. Further, such solid dosage formsmay be uncoated or may be coated by known techniques; e.g., to delaydisintegration and absorption.

[0051] The antitumor compounds of the present invention are alsopreferably formulated for parenteral administration, e.g., formulatedfor injection via intravenous, intraarterial, subcutaneous, rectal,subcutaneous, intramuscular, intraorbital, intracapsular, intraspinal,intraperitoneal, or intrasternal routes. The compositions of theinvention for parenteral administration comprise an effective antitumoramount of the antitumor compound in a pharmaceutically acceptablecarrier. Dosage forms suitable for parenteral administration includesolutions, suspensions, dispersions, emulsions or any other dosage formwhich can be administered parenterally. Techniques and compositions formaking parenteral dosage forms are known in the art.

[0052] Suitable carriers used in formulating liquid dosage forms fororal or parenteral administration include nonaqueous,pharmaceutically-acceptable polar solvents such as oils, alcohols,amides, esters, ethers, ketones, hydrocarbons and mixtures thereof, aswell as water, saline solutions, dextrose solutions (e.g., DW5),electrolyte solutions, or any other aqueous, pharmaceutically acceptableliquid.

[0053] Suitable nonaqueous, pharmaceutically-acceptable polar solventsinclude, but are not limited to, alcohols (e.g., α-glycerol formal,β-glycerol formal, 1, 3-butyleneglycol, aliphatic or aromatic alcoholshaving 2-30 carbon atoms such as methanol, ethanol, propanol,isopropanol, butanol, t-butanol, hexanol, octanol, amylene hydrate,benzyl alcohol, glycerin (glycerol), glycol, hexylene glycol,tetrahydrofurfuryl alcohol, lauryl alcohol, cetyl alcohol, or stearylalcohol, fatty acid esters of fatty alcohols such as polyalkyleneglycols (e.g., polypropylene glycol, polyethylene glycol), sorbitan,sucrose and cholesterol); amides (e.g., dimethylacetamide (DMA), benzylbenzoate DMA, dimethylformamide, N-(β-hydroxyethyl)-lactamide, N,N-dimethylacetamide amides, 2-pyrrolidinone, 1-methyl-2-pyrrolidinone,or polyvinylpyrrolidone); esters (e.g., 1-methyl-2-pyrrolidinone,2-pyrrolidinone, acetate esters such as monoacetin, diacetin, andtriacetin, aliphatic or aromatic esters such as ethyl caprylate oroctanoate, alkyl oleate, benzyl benzoate, benzyl acetate,dimethylsulfoxide (DMSO), esters of glycerin such as mono, di, ortri-glyceryl citrates or tartrates, ethyl benzoate, ethyl acetate, ethylcarbonate, ethyl lactate, ethyl oleate, fatty acid esters of sorbitan,fatty acid derived PEG esters, glyceryl monostearate, glyceride esterssuch as mono, di, or tri-glycerides, fatty acid esters such as isopropylmyristrate, fatty acid derived PEG esters such as PEG-hydroxyoleate andPEG-hydroxystearate, N-methyl pyrrolidinone, pluronic 60,polyoxyethylene sorbitol oleic polyesters such as poly(ethoxylated)₃₀₋₆₀sorbitol poly(oleate)₂₋₄, poly(oxyethylene)₁₅₋₂₀ monooleate,poly(oxyethylene)₁₅₋₂₀ mono 12-hydroxystearate, andpoly(oxyethylene)₁₅₋₂₀ mono ricinoleate, polyoxyethylene sorbitan esterssuch as polyoxyethylene-sorbitan monooleate, polyoxyethylene-sorbitanmonopalmitate, polyoxyethylene-sorbitan monolaurate,polyoxyethylene-sorbitan monostearate, and Polysorbate® 20, 40, 60 or 80from ICI Americas, Wilmington, Del., polyvinylpyrrolidone, alkyleneoxymodified fatty acid esters such as polyoxyl 40 hydrogenated castor oiland polyoxyethylated castor oils (e.g., Cremophor® EL solution orCremophor® RH 40 solution), saccharide fatty acid esters (i.e., thecondensation product of a monosaccharide (e.g., pentoses such as ribose,ribulose, arabinose, xylose, lyxose and xylulose, hexoses such asglucose, fructose, galactose, mannose and sorbose, trioses, tetroses,heptoses, and octoses), disaccharide (e.g., sucrose, maltose, lactoseand trehalose) or oligosaccharide or mixture thereof with a C₄-C₂₂ fattyacid(s)(e.g., saturated fatty acids such as caprylic acid, capric acid,lauric acid, myristic acid, palmitic acid and stearic acid, andunsaturated fatty acids such as palmitoleic acid, oleic acid, elaidicacid, erucic acid and linoleic acid)), or steroidal esters); alkyl,aryl, or cyclic ethers having 2-30 carbon atoms (e.g., diethyl ether,tetrahydrofuran, dimethyl isosorbide, diethylene glycol monoethylether); glycofurol (tetrahydrofurfuryl alcohol polyethylene glycolether); ketones having 3-30 carbon atoms (e.g., acetone, methyl ethylketone, methyl isobutyl ketone); aliphatic, cycloaliphatic or aromatichydrocarbons having 4-30 carbon atoms (e.g., benzene, cyclohexane,dichloromethane, dioxolanes, hexane, n-decane, n-dodecane, n-hexane,sulfolane, tetramethylenesulfon, tetramethylenesulfoxide, toluene,dimethylsulfoxide (DMSO), or tetramethylenesulfoxide); oils of mineral,vegetable, animal, essential or synthetic origin (e.g., mineral oilssuch as aliphatic or wax-based hydrocarbons, aromatic hydrocarbons,mixed aliphatic and aromatic based hydrocarbons, and refined paraffinoil, vegetable oils such as linseed, tung, safflower, soybean, castor,cottonseed, groundnut, rapeseed, coconut, palm, olive, corn, corn germ,sesame, persic and peanut oil and glycerides such as mono-, di- ortriglycerides, animal oils such as fish, marine, sperm, cod-liver,haliver, squalene, squalane, and shark liver oil, oleic oils, andpolyoxyethylated castor oil); alkyl or aryl halides having 1-30 carbonatoms and optionally more than one halogen substituent; methylenechloride; monoethanolamine; petroleum benzin; trolamine; omega-3polyunsaturated fatty acids (e.g., alpha-linolenic acid,eicosapentaenoic acid, docosapentaenoic acid, or docosahexaenoic acid);polyglycol ester of 12-hydroxystearic acid and polyethylene glycol(Solutol® HS-15, from BASF, Ludwigshafen, Germany); polyoxyethyleneglycerol; sodium laurate; sodium oleate; or sorbitan monooleate.

[0054] Other pharmaceutically acceptable solvents for use in theinvention are well known to those of ordinary skill in the art, and areidentified in The Chemotherapy Source Book (Williams & WilkensPublishing), The Handbook of Pharmaceutical Excipients, (AmericanPharmaceutical Association, Washington, D.C., and The PharmaceuticalSociety of Great Britain, London, England, 1968), Modern Pharmaceutics,(G. Banker et al., eds., 3d ed.)(Marcel Dekker, Inc., New York, N.Y.,1995), The Pharmacological Basis of Therapeutics, (Goodman & Gilman,McGraw Hill Publishing), Pharmaceutical Dosage Forms, (H. Lieberman etal., eds., )(Marcel Dekker, Inc., New York, N.Y., 1980), Remington'sPharmaceutical Sciences (A. Gennaro, ed., 19th ed.)(Mack Publishing,Easton, PA, 1995), The United States Pharmacopeia 24, The NationalFormulary 19, (National Publishing, Philadelphia, Pa., 2000), A. J.Spiegel et al., and Use of Nonaqueous Solvents in Parenteral Products,JOURNAL OF PHARMACEUTICAL SCIENCES, Vol. 52, No. 10, pp. 917-927 (1963).

[0055] Preferred solvents include those known to stabilize the antitumorcompounds, such as oils rich in triglycerides, for example, saffloweroil, soybean oil or mixtures thereof, and alkyleneoxy modified fattyacid esters such as polyoxyl 40 hydrogenated castor oil andpolyoxyethylated castor oils (e.g., Cremophor® EL solution or Cremophor®RH 40 solution). Commercially available triglycerides includeIntralipid® emulsified soybean oil (Kabi-Pharmacia Inc., Stockholm,Sweden), Nutralipid ® emulsion (McGaw, Irvine, Calif.), Liposyn® II 20%emulsion (a 20% fat emulsion solution containing 100 mg safflower oil,100 mg soybean oil, 12 mg egg phosphatides, and 25 mg glycerin per ml ofsolution; Abbott Laboratories, Chicago, Ill.), Liposyn® III 2% emulsion(a 2% fat emulsion solution containing 100 mg safflower oil, 100 mgsoybean oil, 12 mg egg phosphatides, and 25 mg glycerin per ml ofsolution; Abbott Laboratories, Chicago, Ill.), natural or syntheticglycerol derivatives containing the docosahexaenoyl group at levelsbetween 25% and 100% by weight based on the total fatty acid content(Dhasco® (from Martek Biosciences Corp., Columbia, Md.), DHA Maguro®(from Daito Enterprises, Los Angeles, Calif.), Soyacal®, andTravemulsion®. Ethanol is a preferred solvent for use in dissolving theantitumor compound to form solutions, emulsions, and the like.

[0056] Additional minor components can be included in the compositionsof the invention for a variety of purposes well known in thepharmaceutical industry. These components will for the most part impartproperties which enhance retention of the antitumor compound at the siteof administration, protect the stability of the composition, control thepH, facilitate processing of the antitumor compound into pharmaceuticalformulations, and the like. Preferably, each of these components isindividually present in less than about 15 weight % of the totalcomposition, more preferably less than about 5 weight %, and mostpreferably less than about 0.5 weight % of the total composition. Somecomponents, such as fillers or diluents, can constitute up to 90 wt. %of the total composition, as is well known in the formulation art. Suchadditives include cryoprotective agents for preventing reprecipitationof the taxane, surface active, wetting or emulsifying agents (e.g.,lecithin, polysorbate-80, Tween® 80, pluronic 60, polyoxyethylenestearate ), preservatives (e.g., ethyl-p-hydroxybenzoate), microbialpreservatives (e.g., benzyl alcohol, phenol, m-cresol, chlorobutanol,sorbic acid, thimerosal and paraben), agents for adjusting pH orbuffering agents (e.g., acids, bases, sodium acetate, sorbitanmonolaurate), agents for adjusting osmolarity (e.g., glycerin),thickeners (e.g., aluminum monostearate, stearic acid, cetyl alcohol,stearyl alcohol, guar gum, methyl cellulose, hydroxypropylcellulose,tristearin, cetyl wax esters, polyethylene glycol), colorants, dyes,flow aids, non-volatile silicones (e.g., cyclomethicone), clays (e.g.,bentonites), adhesives, bulking agents, flavorings, sweeteners,adsorbents, fillers (e.g., sugars such as lactose, sucrose, mannitol, orsorbitol, cellulose, or calcium phosphate), diluents (e.g., water,saline, electrolyte solutions), binders (e.g., starches such as maizestarch, wheat starch, rice starch, or potato starch, gelatin, gumtragacanth, methyl cellulose, hydroxypropyl methylcellulose, sodiumcarboxymethyl cellulose, polyvinylpyrrolidone, sugars, polymers,acacia), disintegrating agents (e.g., starches such as maize starch,wheat starch, rice starch, potato starch, or carboxymethyl starch,cross-linked polyvinyl pyrrolidone, agar, alginic acid or a salt thereofsuch as sodium alginate, croscarmellose sodium or crospovidone),lubricants (e.g., silica, talc, stearic acid or salts thereof such asmagnesium stearate, or polyethylene glycol), coating agents (e.g.,concentrated sugar solutions including gum arabic, talc, polyvinylpyrrolidone, carbopol gel, polyethylene glycol, or titanium dioxide),and antioxidants (e.g., sodium metabisulfite, sodium bisulfite, sodiumsulfite, dextrose, phenols, and thiophenols).

[0057] In a preferred embodiment, a pharmaceutical composition of theinvention comprises at least one nonaqueous, pharmaceutically acceptablesolvent and an antitumor compound having a solubility in ethanol of atleast about 100, 200, 300, 400, 500, 600, 700 or 800 mg/ml. While notbeing bound to a particular theory, it is believed that the ethanolsolubility of the antitumor compound may be directly related to itsefficacy. The antitumor compound can also be capable of beingcrystallized from a solution. In other words, a crystalline antitumorcompound, such as compound 1393, can be dissolved in a solvent to form asolution and then recrystallized upon evaporation of the solvent withoutthe formation of any amorphous antitumor compound. It is also preferredthat the antitumor compound have an ID50 value (i.e, the drugconcentration producing 50% inhibition of colony formation) of at least4, 5, 6, 7, 8, 9, or 10 times less that of paclitaxel when measuredaccording to the protocol set forth in the working examples.

[0058] Dosage form administration by these routes may be continuous orintermittent, depending, for example, upon the patient's physiologicalcondition, whether the purpose of the administration is therapeutic orprophylactic, and other factors known to and assessable by a skilledpractitioner.

[0059] Dosage and regimens for the administration of the pharmaceuticalcompositions of the invention can be readily determined by those withordinary skill in treating cancer. It is understood that the dosage ofthe antitumor compounds will be dependent upon the age, sex, health, andweight of the recipient, kind of concurrent treatment, if any, frequencyof treatment, and the nature of the effect desired. For any mode ofadministration, the actual amount of antitumor compound delivered, aswell as the dosing schedule necessary to achieve the advantageouseffects described herein, will also depend, in part, on such factors asthe bioavailability of the antitumor compound, the disorder beingtreated, the desired therapeutic dose, and other factors that will beapparent to those of skill in the art. The dose administered to ananimal, particularly a human, in the context of the present inventionshould be sufficient to effect the desired therapeutic response in theanimal over a reasonable period of time. Preferably, an effective amountof the antitumor compound, whether administered orally or by anotherroute, is any amount which would result in a desired therapeuticresponse when administered by that route. Preferably, the compositionsfor oral administration are prepared in such a way that a single dose inone or more oral preparations contains at least 20 mg of the antitumorcompound per m² of patient body surface area, or at least 50, 100, 150,200, 300, 400, or 500 mg of the antitumor compound per m² of patientbody surface area, wherein the average body surface area for a human is1.8 m². Preferably, a single dose of a composition for oraladministration contains from about 20 to about 600 mg of the antitumorcompound per m² of patient body surface area, more preferably from about25 to about 400 mg/m² even more preferably, from about 40 to about 300mg/m², and even more preferably from about 50 to about 200 mg/m².Preferably, the compositions for parenteral administration are preparedin such a way that a single dose contains at least 20 mg of theantitumor compound per m² of patient body surface area, or at least 40,50, 100, 150, 200, 300, 400, or 500 mg of the antitumor compound per m²of patient body surface area. Preferably, a single dose in one or moreparenteral preparations contains from about 20 to about 500 mg of theantitumor compound per m² of patient body surface area, more preferablyfrom about 40 to about 400 mg/m^(2′) and even more preferably, fromabout 60 to about 350 mg/m². However, the dosage may vary depending onthe dosing schedule which can be adjusted as necessary to achieve thedesired therapeutic effect. It should be noted that the ranges ofeffective doses provided herein are not intended to limit the inventionand represent preferred dose ranges. The most preferred dosage will betailored to the individual subject, as is understood and determinable byone of ordinary skill in the art without undue experimentation.

[0060] The concentration of the antitumor compound in a liquidpharmaceutical composition is preferably between about 0.01 mg and about10 mg per ml of the composition, more preferably between about 0.1 mgand about 7 mg per ml, even more preferably between about 0.5 mg andabout 5 mg per ml, and most preferably between about 1.5 mg and about 4mg per ml. Relatively low concentrations are generally preferred becausethe antitumor compound is most soluble in the solution at lowconcentrations. The concentration of the antitumor compound in a solidpharmaceutical composition for oral administration is preferably betweenabout 5 weight % and about 50 weight %, based on the total weight of thecomposition, more preferably between about 8 weight % and about 40weight %, and most preferably between about 10 weight % and about 30weight %.

[0061] In one embodiment, solutions for oral administration are preparedby dissolving an antitumor compound in any pharmaceutically acceptablesolvent capable of dissolving the compound (e.g., ethanol or methylenechloride) to form a solution. An appropriate volume of a carrier whichis a solution, such as Cremophor® EL solution, is added to the solutionwhile stirring to form a pharmaceutically acceptable solution for oraladministration to a patient. If desired, such solutions can beformulated to contain a minimal amount of, or to be free of, ethanol,which is known in the art to cause adverse physiological effects whenadministered at certain concentrations in oral formulations.

[0062] In another embodiment, powders or tablets for oral administrationare prepared by dissolving an antitumor compound in any pharmaceuticallyacceptable solvent capable of dissolving the compound (e.g.,ethanol ormethylene chloride) to form a solution. The solvent can optionally becapable of evaporating when the solution is dried under vacuum. Anadditional carrier can be added to the solution prior to drying, such asCremophor® EL solution. The resulting solution is dried under vacuum toform a glass. The glass is then mixed with a binder to form a powder.The powder can be mixed with fillers or other conventional tablettingagents and processed to form a tablet for oral administration to apatient. The powder can also be added to any liquid carrier as describedabove to form a solution, emulsion, suspension or the like for oraladministration.

[0063] Emulsions for parenteral administration can be prepared bydissolving an antitumor compound in any pharmaceutically acceptablesolvent capable of dissolving the compound (e.g., ethanol or methylenechloride) to form a solution. An appropriate volume of a carrier whichis an emulsion, such as Liposyn® II or Liposyn® III emulsion, is addedto the solution while stirring to form a pharmaceutically acceptableemulsion for parenteral administration to a patient. If desired, suchemulsions can be formulated to contain a minimal amount of, or to befree of, ethanol or Cremophor® solution, which are known in the art tocause adverse physiological effects when administered at certainconcentrations in parenteral formulations.

[0064] Solutions for parenteral administration can be prepared bydissolving an antitumor compound in any pharmaceutically acceptablesolvent capable of dissolving the compound (e.g., ethanol or methylenechloride) to form a solution. An appropriate volume of a carrier whichis a solution, such as Cremophor® solution, is added to the solutionwhile stirring to form a pharmaceutically acceptable solution forparenteral administration to a patient. If desired, such solutions canbe formulated to contain a minimal amount of, or to be free of, ethanolor Cremophor® solution, which are known in the art to cause adversephysiological effects when administered at certain concentrations inparenteral formulations.

[0065] If desired, the emulsions or solutions described above for oralor parenteral administration can be packaged in IV bags, vials or otherconventional containers in concentrated form and diluted with anypharmaceutically acceptable liquid, such as saline, to form anacceptable taxane concentration prior to use as is known in the art.

[0066] Definitions

[0067] The terms “hydrocarbon” and “hydrocarbyl” as used herein describeorganic compounds or radicals consisting exclusively of the elementscarbon and hydrogen. These moieties include alkyl, alkenyl, alkynyl, andaryl moieties. These moieties also include alkyl, alkenyl, alkynyl, andaryl moieties substituted with other aliphatic or cyclic hydrocarbongroups, such as alkaryl, alkenaryl and alkynaryl. Unless otherwiseindicated, these moieties preferably comprise 1 to 20 carbon atoms.

[0068] The “substituted hydrocarbyl” moieties described herein arehydrocarbyl moieties which are substituted with at least one atom otherthan carbon, including moieties in which a carbon chain atom issubstituted with a hetero atom such as nitrogen, oxygen, silicon,phosphorous, boron, sulfur, or a halogen atom. These substituentsinclude halogen, heterocyclo, alkoxy, alkenoxy, alkynoxy, aryloxy,hydroxy, protected hydroxy, keto, acyl, acyloxy, nitro, amino, amido,nitro, cyano, thiol, ketals, acetals, esters and ethers.

[0069] Unless otherwise indicated, the alkyl groups described herein arepreferably lower alkyl containing from one to eight carbon atoms in theprincipal chain and up to 20 carbon atoms. They may be straight orbranched chain or cyclic and include methyl, ethyl, propyl, isopropyl,butyl, hexyl and the like.

[0070] Unless otherwise indicated, the alkenyl groups described hereinare preferably lower alkenyl containing from two to eight carbon atomsin the principal chain and up to 20 carbon atoms. They may be straightor branched chain or cyclic and include ethenyl, propenyl, isopropenyl,butenyl, isobutenyl, hexenyl, and the like.

[0071] Unless otherwise indicated, the alkynyl groups described hereinare preferably lower alkynyl containing from two to eight carbon atomsin the principal chain and up to 20 carbon atoms. They may be straightor branched chain and include ethynyl, propynyl, butynyl, isobutynyl,hexynyl, and the like.

[0072] The terms “aryl” or “ar” as used herein alone or as part ofanother group denote optionally substituted homocyclic aromatic groups,preferably monocyclic or bicyclic groups containing from 6 to 12 carbonsin the ring portion, such as phenyl, biphenyl, naphthyl, substitutedphenyl, substituted biphenyl or substituted naphthyl. Phenyl andsubstituted phenyl are the more preferred aryl.

[0073] The terms “halogen” or “halo” as used herein alone or as part ofanother group refer to chlorine, bromine, fluorine, and iodine.

[0074] The terms “heterocyclo” or “heterocyclic” as used herein alone oras part of another group denote optionally substituted, fully saturatedor unsaturated, monocyclic or bicyclic, aromatic or nonaromatic groupshaving at least one heteroatom in at least one ring, and preferably 5 or6 atoms in each ring. The heterocyclo group preferably has 1 or 2 oxygenatoms, 1 or 2 sulfur atoms, and/or 1 to 4 nitrogen atoms in the ring,and may be bonded to the remainder of the molecule through a carbon orheteroatom. Exemplary heterocyclo include heteroaromatics such as furyl,thienyl, pyridyl, oxazolyl, pyrrolyl, indolyl, quinolinyl, orisoquinolinyl and the like. Exemplary substituents include one or moreof the following groups: hydrocarbyl, substituted hydrocarbyl, keto,hydroxy, protected hydroxy, acyl, acyloxy, alkoxy, alkenoxy, alkynoxy,aryloxy, halogen, amido, amino, nitro, cyano, thiol, ketals, acetals,esters and ethers.

[0075] The term “heteroaromatic” as used herein alone or as part ofanother group denote optionally substituted aromatic groups having atleast one heteroatom in at least one ring, and preferably 5 or 6 atomsin each ring. The heteroaromatic group preferably has 1 or 2 oxygenatoms, 1 or 2 sulfur atoms, and/or 1 to 4 nitrogen atoms in the ring,and may be bonded to the remainder of the molecule through a carbon orheteroatom. Exemplary heteroaromatics include furyl, thienyl, pyridyl,oxazolyl, pyrrolyl, indolyl, quinolinyl, or isoquinolinyl and the like.Exemplary substituents include one or more of the following groups:hydrocarbyl, substituted hydrocarbyl, keto, hydroxy, protected hydroxy,acyl, acyloxy, alkoxy, alkenoxy, alkynoxy, aryloxy, halogen, amido,amino, nitro, cyano, thiol, ketals, acetals, esters and ethers.

[0076] The term “acyl,” as used herein alone or as part of anothergroup, denotes the moiety formed by removal of the hydroxyl group fromthe group —COOH of an organic carboxylic acid, e.g., RC(O)—, wherein Ris R¹, R¹O—, R¹R²N—, or R¹S—, R¹ is hydrocarbyl, heterosubstitutedhydrocarbyl, or heterocyclo and R² is hydrogen, hydrocarbyl orsubstituted hydrocarbyl.

[0077] The term “acyloxy,” as used herein alone or as part of anothergroup, denotes an acyl group as described above bonded through an oxygenlinkage (—O—), e.g., RC(O)O— wherein R is as defined in connection withthe term “acyl.” Unless otherwise indicated, the alkoxycarbonyloxymoieties described herein comprise lower hydrocarbon or substitutedhydrocarbon or substituted hydrocarbon moieties.

[0078] Unless otherwise indicated, the carbamoyloxy moieties describedherein are derivatives of carbamic acid in which one or both of theamine hydrogens is optionally replaced by a hydrocarbyl, substitutedhydrocarbyl or heterocyclo moiety.

[0079] The terms “hydroxyl protecting group” and “hydroxy protectinggroup” as used herein denote a group capable of protecting a freehydroxyl group (“protected hydroxyl”) which, subsequent to the reactionfor which protection is employed, may be removed without disturbing theremainder of the molecule. A variety of protecting groups for thehydroxyl group and the synthesis thereof may be found in “ProtectiveGroups in Organic Synthesis” by T. W. Greene, John Wiley and Sons, 1981,or Fieser & Fieser. Exemplary hydroxyl protecting groups includemethoxymethyl, 1-ethoxyethyl, benzyloxymethyl,(.beta.-trimethylsilylethoxy)methyl, tetrahydropyranyl,2,2,2-trichloroethoxycarbonyl, t-butyl(d iphenyl)silyl, trialkylsilyl,trichloromethoxycarbonyl and 2,2,2-trichloroethoxymethyl.

[0080] As used herein, “Ac” means acetyl; “Bz” means benzoyl; “Et” meansethyl; “Me” means methyl; “Ph” means phenyl; “iPr” means isopropyl;“tBu” and “t-Bu” means tert-butyl; “R” means lower alkyl unlessotherwise defined; “py” means pyridine or pyridyl; “TES” meanstriethylsilyl; “TMS” means trimethylsilyl; “LAH” means lithium aluminumhydride; “10-DAB” means 10-desacetylbaccatin III”; “amine protectinggroup” includes, but is not limited to, carbamates, for example,2,2,2-trichloroethylcarbamate or tertbutylcarbamate; “protected hydroxy”means—OP wherein P is a hydroxy protecting group; “tBuOCO” and “Boc”mean tert-butoxycarbonyl; “tAmOCO” means tert-amyloxycarbonyl; “2-FuCO”means 2-furylcarbonyl; “2-ThCO” means 2-thienylcarbonyl; “2-PyCO” means2-pyridylcarbonyl; “3-PyCO” means 3-pyridylcarbonyl; “4-PyCO” means4-pyridylcarbonyl; “C₄H₇CO” means butenylcarbonyl; “EtOCO” meansethoxycarbonyl; “ibueCO” means isobutenylcarbonyl; “iBuCO” meansisobutylcarbonyl; “iBuOCO” means isobutoxycarbonyl; “iPrOCO” meansisopropyloxycarbonyl; “nPrOCO” means n-propyloxycarbonyl; “nPrCO” meansn-propylcarbonyl; “ibue” means isobutenyl; “THF” means tetrahydrofuran;“DMAP” means 4-dimethylamino pyridine; “LHMDS” means LithiumHexamethylDiSilazanide.

[0081] The following examples illustrate the invention.

EXAMPLE 1

[0082]

[0083] 7,10-(bis)-carbobenzyloxy-10-deacetyl baccatin III. To a solutionof 10-DAB (1.14 g, 2.11 mmol) in 20 mL of methylene chloride was addedDMAP (6.20 g, 50.6 mmol) and benzyl chloroformate (1.8 mL, 12.7 mmol)slowly under a nitrogen atmosphere. The mixture was heated to 40-45° C.,kept at this temperature for 2 h, and an additional 1.8 mL (12.7 mmol)of benzyl chloroformate was added. Heating at 40-45° C. was continuedfor an additional 6 h, the mixture was diluted with 200 mL of CH₂Cl₂ andwashed three times first with 1N HCl and then with saturated sodiumbicarbonate solution. The combined washings were extracted three timeswith 30 mL of CH₂Cl_(2,) the organic layers were combined, washed withbrine, dried over Na₂SO₄, and concentrated under reduced pressure.Chromatography of the residue on silica gel eluting with CH₂Cl₂/EtOAcgave 1.48 g (86%) of 7,1 0-(bis)-carbobenzyloxy-10-deacetyl baccatinIII.

[0084]7,10-(bis)-carbobenzyloxy-3′-desphenyl-3′-(2-thienyl)-2′-O-triethylsilyldocetaxel. To a solution of 425 mg (0.523 mmol) of7,10-(bis)-carbobenzyloxy-10-deacetyl baccatin III in THF (4.5 mL) at−45° C. under a nitrogen atmosphere was added 0.80 mL of a solution ofLHMDS (0.98 M) in THF dropwise. The mixture was kept at −45° C. for 1 hprior to addition of a solution of 341 mg (0.889 mmol) ofcis-N-tbutoxycarbonyl-3-triethylsilyloxy-4-(2-thienyl) azetidin-2-one in2 mL of THF. The mixture was allowed to warm to 0° C., and after 2 h waspoured into 20 mL of saturated ammonium chloride solution. The aqueouslayer was extracted three times with 50 mL of EtOAc/Hexanes (1:1) andthe organic layers were combined, washed with brine, dried over Na₂SO₄and concentrated. Chromatography of the residue on silica gel elutingwith EtOAc/Hexanes gave 576 mg (92%) of7,10-(bis)-carbobenzyloxy-3′-desphenyl-3′-(2-thienyl)-2′-O-triethylsilyldocetaxel.

[0085] 3′-Desphenyl-3′-(2-thienyl)-2′-O-triethylsilyl docetaxel. Asuspension of 550 mg of7,10-(bis)-carbobenzyloxy-3′-desphenyl-3′-(2-thienyl)-2′-O-triethylsilyldocetaxel and 50 mg of 10% Pd/C in 30 mL of EtOH and 10 mL of EtOAc wasstirred under a hydrogen atmosphere for 2 h at room temperature. Theslurry was filtered through a pad of celite 545 which was then washedwith EtOAc. The washings were concentrated and the residue was purifiedby column chromatography on silica gel using EtOAc/Hexanes as eluent togive 405 mg (95%) of 3′-desphenyl-3′-(2-thienyl)-2′-O-triethylsilyldocetaxel.

[0086]3′-Desphenyl-3′-(2-thienyl)-2′-O-triethylsilyi-10-N-ethylcarbamoyldocetaxel. To a slurry of 3′-desphenyl-3′-(2-thienyl)-2′-O-triethylsilyldocetaxel (201 mg, 0.217 mmol) and CuCl (43.0 mg, 0.434 mmol) in THF(3.5 mL) at −15° C. under a nitrogen atmosphere was added a solution of51.5 mL (0.651 mmol) of ethyl isocynate in 1.9 mL of THF. The mixturewas warmed to 0° C. and after 1.4 h 5mL of saturated aqueous sodiumbicarbonate solution and 20 mL of ethyl acetate were added. The waterlayer was extracted three times with 50 mL of EtOAc/Hexanes (1:1). Theorganic layers were combined, dried over Na₂SO₄ and evaporated to give218 mg of a residue which was used directly without purification.

[0087] 3′-D sphenyl-3′-(2-thienyl)-10-N— thylcarbamoyl docetaxel (2722).To a solution of the 218 mg of3′-desphenyl-3′-(2-thienyl)-2′-O-triethylsilyl-10-N-ethylcarbamoyldocetaxel obtained above in 6 mL of pyridine and 12 mL of CH₃CN at 0° C.was added 1.0 mL of 49% aqueous HF. The mixture was warmed to roomtemperature and after 2.5 h 50 mL of EtOAc was added. The mixture waswashed with saturated aqueous sodium bicarbonate solution and brine,dried over sodium sulfate, and concentrated under reduced pressure.Chromatography of the residue on silica gel using CH₂Cl₂/MeOH as eluentgave 169 mg (88% for 2 steps) of3′-desphenyl-3′-(2-thienyl)-10-N-ethylcarbamoyl docetaxel (2722).

EXAMPLE 2

[0088] The procedures described in Example 1 were repeated, but othersuitably protected β-lactams and acylating agents were substituted forthe β-lactam and acylating agent of Example 1 to prepare the series ofcompounds having the combination of substituents identified in thefollowing table. The following table also includes characterization datafor certain of these compounds, along with characterization data for thecompound (2722) prepared in Example 1.

No. X₃ m.p. (° C.) [α]_(D)(CHCl₃) Elemental Analysis 2600 2-pyridyl173-175 −71.4 (c 0.22) Found: C, 60.70; H, 6.69 (Calcd. forC₄₅H₅₇N₃O₁₅.0.5H₂O: C, 60.79; H, 6.58) 2616 3-pyridyl 183-185 −61.0 (c0.20) Found: C, 58.96; H, 6.51 (Calcd. for C₄₅H₅₇N₃O₁₅.2H₂O: C, 59.00;H, 6.69) 2622 3-thienyl 173-175 −68.1 (c 0.19) Found: C, 58.40; H, 6.42(Calcd. for C₄₄H₅₆N₂O₁₅S.H₂O: C, 58.47; H, 6.47) 2633 i-propyl 170-172−75.7 (c 0.22) Found: C, 60.10; H, 7.15 (Calcd. for C₄₃H₆₀N₂O₁₅.H₂O: C,59.84; H, 7.24) 2686 i-butenyl 167-169 −106.7 (c 0.17)  Found: C, 61.12;H, 7.10 (Calcd. for C₄₄H₆₀N₂O₁₅.0.5H₂O: C, 61.02; H, 7.10) 26924-pyridyl 203-205 −69.7 (c 0.18) Found: C, 60.19; H, 6.61 (Calcd. forC₄₅H₅₇N₃O₁₅.H₂O: C, 60.13; H, 6.62) 2700 2-furyl 169-171 −73.6 (C 0.22)Found: C, 60.59; H, 6.58 (Calcd. for C₄₄H₅₆N₂O₁₆: C, 60.82; H, 6.50)2717 3-furyl 165-167 −53.8 (c 0.23) Found: C, 60.07; H, 6.48 (Calcd. forC₄₄H₅₆N₂O₁₆.0.5H₂O: C, 60.14; H, 6.54) 2722 2-thienyl 166-168 −52.2 (c0.25) Found: C, 58.28; H, 6.32 (Calcd. for C₄₄H₅₆N₂O₁₅S.H₂O: C, 58.47;H, 6.47) 2733 cyclobutyl 168-170 −73.9 (c 0.23) Found: C, 60.96; H, 7.02(Calcd. for C₄₄H₆₀N₂O₁₅0.5H₂O: C, 61.02; H, 7.10) 2757 cyclopropyl168-170 −91.7 (c 0.23) Found: C, 60.07; H, 6.86 (Calcd. forC₄₃H₅₅N₂O₁₅.H₂O: C, 59.98; H,7.02)

EXAMPLE 3

[0089] The procedures described in Example 1 were repeated, but othersuitably protected β-lactams and were substituted for thecis-N-tbutoxycarbonyl-3-triethylsilyloxy-4-(2-thienyl) azetidin-2-one ofExample 1 to prepare the series of compounds corresponding to structure14 and having the combination of substituents identified in thefollowing table.

Compound X₅ X₃ R₁₀ 2640 tBuOCO— phenyl EtNHCOO— 2743 tRuOCO—p-nitrophenyl EtNHCOO— 6015 tC₃H₅CO— 2-furyl 3,4diFPhNHCOO— 6024tC₃H₅CO— 2-furyl PhNHCOO— 6072 tC₃H₅CO— 2-furyl EtNHCOO—

EXAMPLE 4

[0090] Following the processes described in Example 1 and elsewhereherein, the following specific taxanes having structural formula 14 andthe combinations of substituents identified in the following table maybe prepared, wherein R₁₀ is as previously defined including wherein R₁₀is R_(10a)R_(10b)NCOO— and (a) R_(10a) and R_(10b) are each hydrogen,(b) one of R_(10a) and R_(10b) is hydrogen and the other is (i)substituted or unsubstituted C₁ to C₈ alkyl such as methyl, ethyl, orstraight, branched or cyclic propyl, butyl, pentyl, or hexyl; (ii)substituted or unsubstituted C₃ to C₈ alkenyl such as ethenyl orstraight, branched or cyclic propenyl, butenyl, pentenyl or hexenyl;(iii) substituted or unsubstituted C₃ to C₈ alkynyl such as ethynyl orstraight or branched propynyl, butynyl, pentynyl, or hexynyl; (iv)substituted or unsubstituted phenyl, or (v) substituted or unsubstitutedheteroaromatic such as furyl, thienyl, or pyridyl, or (c) R_(10a) andR_(10b) are independently (i) substituted or unsubstituted C₁ to C₈alkyl such as methyl, ethyl, or straight, branched or cyclic propyl,butyl, pentyl, or hexyl; (ii) substituted or unsubstituted C₂ to C₈alkenyl such as ethenyl or straight, branched or cyclic propenyl,butenyl, pentenyl or hexenyl; (iii) substituted or unsubstituted C₂ toC₈ alkynyl such as ethynyl or straight or branched propynyl, butynyl,pentynyl, or hexynyl; (iv) substituted or unsubstituted phenyl, or (v)substituted or unsubstituted heteroaromatic such as furyl, thienyl, orpyridyl. For example, R₁₀ may be R_(10a)R_(10b)NCOO— wherein one ofR_(10a) and R_(10b) is hydrogen and the other is methyl, ethyl, orstraight, branched or cyclic propyl. The substituents may be thoseidentified elsewhere herein for substituted hydrocarbyl.

X₅ X₃ R₁₀ tBuOCO 2-furyl R_(10a)R_(10b)NCOO— tBuOCO 3-furylR_(10a)R_(10b)NCOO— tBuOCO 2-thienyl R_(10a)R_(10b)NCOO— tBuOCO3-thienyl R_(10a)R_(10b)NCOO— tBuOCO 2-pyridyl R_(10a)R_(10b)NCOO—tBuOCO 3-pyridyl R_(10a)R_(10b)NCOO— tBuOCO 4-pyridylR_(10a)R_(10b)NCOO— tBuOCO isobutenyl R_(10a)R_(10b)NCOO— tBuOCOisopropyl R_(10a)R_(10b)NCOO— tBuOCO cyclopropyl R_(10a)R_(10b)NCOO—tBuOCO cyclobutyl R_(10a)R_(10b)NCOO— tBuOCO cyclopentylR_(10a)R_(10b)NCOO— tBuOCO phenyl R_(10a)R_(10b)NCOO— benzoyl 2-furylR_(10a)R_(10b)NCOO— benzoyl 3-furyl R_(10a)R_(10b)NCOO— benzoyl2-thienyl R_(10a)R_(10b)NCOO— benzoyl 3-thienyl R_(10a)R_(10b)NCOO—benzoyl 2-pyridyl R_(10a)R_(10b)NCOO— benzoyl 3-pyridylR_(10a)R_(10b)NCOO— benzoyl 4-pyridyl R_(10a)R_(10b)NCOO— benzoylisobutenyl R_(10a)R_(10b)NCOO— benzoyl isopropyl R_(10a)R_(10b)NCOO—benzoyl cyclopropyl R_(10a)R_(10b)NCOO— benzoyl cyclobutylR_(10a)R_(10b)NCOO— benzoyl cyclopentyl R_(10a)R_(10b)NCOO— benzoylphenyl R_(10a)R_(10b)NCOO— 2-FuCO— 2-furyl R_(10a)R_(10b)NCOO— 2-FuCO—3-furyl R_(10a)R_(10b)NCOO— 2-FuCO— 2-thienyl R_(10a)R_(10b)NCOO—2-FuCO— 3-thienyl R_(10a)R_(10b)NCOO— 2-FuCO— 2-pyridylR_(10a)R_(10b)NCOO— 2-FuCO— 3-pyridyl R_(10a)R_(10b)NCOO— 2-FuCO—4-pyridyl R_(10a)R_(10b)NCOO— 2-FuCO— isobutenyl R_(10a)R_(10b)NCOO—2-FuCO— isopropyl R_(10a)R_(10b)NCOO— 2-FuCO— cyclopropylR_(10a)R_(10b)NCOO— 2-FuCO— cyclobutyl R_(10a)R_(10b)NCOO— 2-FuCO—cyclopentyl R_(10a)R_(10b)NCOO— 2-FuCO— phenyl R_(10a)R_(10b)NCOO—2-ThCO— 2-furyl R_(10a)R_(10b)NCOO— 2-ThCO— 3-furyl R_(10a)R_(10b)NCOO—2-ThCO— 2-thienyl R_(10a)R_(10b)NCOO— 2-ThCO— 3-thienylR_(10a)R_(10b)NCOO— 2-ThCO— 2-pyridyl R_(10a)R_(10b)NCOO— 2-ThCO—3-pyridyl R_(10a)R_(10b)NCOO— 2-ThCO— 4-pyridyl R_(10a)R_(10b)NCOO—2-ThCO— isobutenyl R_(10a)R_(10b)NCOO— 2-ThCO— isopropylR_(10a)R_(10b)NCOO— 2-ThCO— cyclopropyl R_(10a)R_(10b)NCOO— 2-ThCO—cyclobutyl R_(10a)R_(10b)NCOO— 2-ThCO— cyclopentyl R_(10a)R_(10b)NCOO—2-ThCO— phenyl R_(10a)R_(10b)NCOO— 2-PyCO— 2-furyl R_(10a)R_(10b)NCOO—2-PyCO— 3-furyl R_(10a)R_(10b)NCOO— 2-PyCO— 2-thienylR_(10a)R_(10b)NCOO— 2-PyCO— 3-thienyl R_(10a)R_(10b)NCOO— 2-PyCO—2-pyridyl R_(10a)R_(10b)NCOO— 2-PyCO— 3-pyridyl R_(10a)R_(10b)NCOO—2-PyCO— 4-pyridyl R_(10a)R_(10b)NCOO— 2-PyCO— isobutenylR_(10a)R_(10b)NCOO— 2-PyCO— isopropyl R_(10a)R_(10b)NCOO— 2-PyCO—cyclopropyl R_(10a)R_(10b)NCOO— 2-PyCO— cyclobutyl R_(10a)R_(10b)NCOO—2-PyCO— cyclopentyl R_(10a)R_(10b)NCOO— 2-PyCO— phenylR_(10a)R_(10b)NCOO— 3-PyCO— 2-furyl R_(10a)R_(10b)NCOO— 3-PyCO— 3-furylR_(10a)R_(10b)NCOO— 3-PyCO— 2-thienyl R_(10a)R_(10b)NCOO— 3-PyCO—3-thienyl R_(10a)R_(10b)NCOO— 3-PyCO— 2-pyridyl R_(10a)R_(10b)NCOO—3-PyCO— 3-pyridyl R_(10a)R_(10b)NCOO— 3-PyCO— 4-pyridylR_(10a)R_(10b)NCOO— 3-PyCO— isobutenyl R_(10a)R_(10b)NCOO— 3-PyCO—isopropyl R_(10a)R_(10b)NCOO— 3-PyCO— cyclopropyl R_(10a)R_(10b)NCOO—3-PyCO— cyclobutyl R_(10a)R_(10b)NCOO— 3-PyCO— cyclopentylR_(10a)R_(10b)NCOO— 3-PyCO— phenyl R_(10a)R_(10b)NCOO— 4-PyCO— 2-furylR_(10a)R_(10b)NCOO— 4-PyCO— 3-furyl R_(10a)R_(10b)NCOO— 4-PyCO—2-thienyl R_(10a)R_(10b)NCOO— 4-PyCO— 3-thienyl R_(10a)R_(10b)NCOO—4-PyCO— 2-pyridyl R_(10a)R_(10b)NCOO— 4-PyCO— 3-pyridylR_(10a)R_(10b)NCOO— 4-PyCO— 4-pyridyl R_(10a)R_(10b)NCOO— 4-PyCO—isobutenyl R_(10a)R_(10b)NCOO— 4-PyCO— isopropyl R_(10a)R_(10b)NCOO—4-PyCO— cyclopropyl R_(10a)R_(10b)NCOO— 4-PyCO— cyclobutylR_(10a)R_(10b)NCOO— 4-PyCO— cyclopentyl R_(10a)R_(10b)NCOO— 4-PyCO—phenyl R_(10a)R_(10b)NCOO— C₄H₇CO— 2-furyl R_(10a)R_(10b)NCOO— C₄H₇CO—3-fuiyl R_(10a)R_(10b)NCOO— C₄H₇CO— 2-thienyl R_(10a)R_(10b)NCOO—C₄H₇CO— 3-thienyl R_(10a)R_(10b)NCOO— C₄H₇CO— 2-pyridylR_(10a)R_(10b)NCOO— C₄H₇CO— 3-pyridyl R_(10a)R_(10b)NCOO— C₄H₇CO—4-pyridyl R_(10a)R_(10b)NCOO— C₄H₇CO— isobutenyl R_(10a)R_(10b)NCOO—C₄H₇CO— isopropyl R_(10a)R_(10b)NCOO— C₄H₇CO— cyclopropylR_(10a)R_(10b)NCOO— C₄H₇CO— cyclobutyl R_(10a)R_(10b)NCOO— C₄H₇CO—cyclopentyl R_(10a)R_(10b)NCOO— C₄H₇CO— phenyl R_(10a)R_(10b)NCOO— EtOCO2-furyl R_(10a)R_(10b)NCOO— EtOCO 3-furyl R_(10a)R_(10b)NCOO— EtOCO—2-thienyl R_(10a)R_(10b)NCOO— EtOCO— 3-thienyl R_(10a)R_(10b)NCOO—EtOCO— 2-pyridyl R_(10a)R_(10b)NCOO— EtOCO— 3-pyridylR_(10a)R_(10b)NCOO— EtOCO— 4-pyridyl R_(10a)R_(10b)NCOO— EtOCO—isobutenyl R_(10a)R_(10b)NCOO— EtOCO— isopropyl R_(10a)R_(10b)NCOO—EtOCO— cyclopropyl R_(10a)R_(10b)NCOO— EtOCO— cyclobutylR_(10a)R_(10b)NCOO— EtOCO— cyclopentyl R_(10a)R_(10b)NCOO— EtOCO— phenylR_(10a)R_(10b)NCOO— ibueCO— 2-furyl R_(10a)R_(10b)NCOO— ibueCO— 3-furylR_(10a)R_(10b)NCOO— ibueCO— 2-thienyl R_(10a)R_(10b)NCOO— ibueCO—3-thienyl R_(10a)R_(10b)NCOO— ibueCO— 2-pyridyl R_(10a)R_(10b)NCOO—ibueCO— 3-pyridyl R_(10a)R_(10b)NCOO— ibueCO— 4-pyridylR_(10a)R_(10b)NCOO— ibueCO— isobutenyl R_(10a)R_(10b)NCOO— ibueCO—isopropyl R_(10a)R_(10b)NCOO— ibueCO— cyclopropyl R_(10a)R_(10b)NCOO—ibueCO— cyclobutyl R_(10a)R_(10b)NCOO— ibueCO— cyclopentylR_(10a)R_(10b)NCOO— ibueCO— phenyl R_(10a)R_(10b)NCOO— iBuCO— 2-furylR_(10a)R_(10b)NCOO— iBuCO— 3-furyl R_(10a)R_(10b)NCOO— iBuCO— 2-thienylR_(10a)R_(10b)NCOO— iBuCO— 3-thienyl R_(10a)R_(10b)NCOO— iBuCO—2-pyridyl R_(10a)R_(10b)NCOO— iBuCO— 3-pyridyl R_(10a)R_(10b)NCOO—iBuCO— 4-pyridyl R_(10a)R_(10b)NCOO— IBuCO— isobutenylR_(10a)R_(10b)NCOO— iBuCO— isopropyl R_(10a)R_(10b)NCOO— iBuCO—cyclopropyl R_(10a)R_(10b)NCOO— iBuCO— cyclobutyl R_(10a)R_(10b)NCOO—iBuCO— cyclopentyl R_(10a)R_(10b)NCOO— iBuCO— phenyl R_(10a)R_(10b)NCOO—iBuOCO— 2-fuiyI R_(10a)R_(10b)NCOO— iBuOCO— 3-furyl R_(10a)R_(10b)NCOO—iBuOCO— 2-thienyl R_(10a)R_(10b)NCOO— iBuOCO— 3-thienylR_(10a)R_(10b)NCOO— iBuOCO— 2-pyridyl R_(10a)R_(10b)NCOO— iBuOCO—3-pyridyl R_(10a)R_(10b)NCOO— iBuOCO— 4-pyridyl R_(10a)R_(10b)NCOO—iBuOCO— isobutenyl R_(10a)R_(10b)NCOO— iBuOCO— isopropylR_(10a)R_(10b)NCOO— iBuOCO— cyclopropyl R_(10a)R_(10b)NCOO— iBuOCO—cyclobutyl R_(10a)R_(10b)NCOO— iBuOCO— cyclopentyl R_(10a)R_(10b)NCOO—iBuOCO— phenyl R_(10a)R_(10b)NCOO— iPrOCO— 2-furyl R_(10a)R_(10b)NCOO—iPrOCO— 3-furyl R_(10a)R_(10b)NCOO— iPrOCO— 2-thienylR_(10a)R_(10b)NCOO— iPrOCO— 3-thienyl R_(10a)R_(10b)NCOO— iPrOCO—2-pyridyl R_(10a)R_(10b)NCOO— iPrOCO— 3-pyridyl R_(10a)R_(10b)NCOO—iPrOCO— 4-pyridyl R_(10a)R_(10b)NCOO— iPrOCO— isobutenylR_(10a)R_(10b)NCOO— iPrOCO— isopropyl R_(10a)R_(10b)NCOO— iPrOCO—cyclopropyl R_(10a)R_(10b)NCOO— iPrOCO— cyclobutyl R_(10a)R_(10b)NCOO—iPrOCO— cyclopentyl R_(10a)R_(10b)NCOO— iPrOCO— phenylR_(10a)R_(10b)NCOO— iPrOCO— 2-furyl R_(10a)R_(10b)NCOO— nPrOCO— 3-furylR_(10a)R_(10b)NCOO— nPrOCO— 2-thienyl R_(10a)R_(10b)NCOO— nPrOCO—3-thienyl R_(10a)R_(10b)NCOO— nPrOCO— 2-pyridyl R_(10a)R_(10b)NCOO—nPrOCO— 3-pyridyl R_(10a)R_(10b)NCOO— nPrOCO— 4-pyridylR_(10a)R_(10b)NCOO— nPrOCO— isobutenyl R_(10a)R_(10b)NCOO— nPrOCO—isopropyl R_(10a)R_(10b)NCOO— nPrOCO— cyclopropyl R_(10a)R_(10b)NCOO—nPrOCO— cyclobutyl R_(10a)R_(10b)NCOO— nPrOCO— cyclopentylR_(10a)R_(10b)NCOO— nPrOCO— phenyl R_(10a)R_(10b)NCOO— nPrCO— 2-furylR_(10a)R_(10b)NCOO— nPrCO— 3-furyl R_(10a)R_(10b)NCOO— nPrCO— 2-thienylR_(10a)R_(10b)NCOO— nPrCO— 3-thienyl R_(10a)R_(10b)NCOO— nPrCO—2-pyridyl R_(10a)R_(10b)NCOO— nPrCO— 3-pyridyl R_(10a)R_(10b)NCOO—nPrCO— 4-pyridyl R_(10a)R_(10b)NCOO— nPrCO— isobutenylR_(10a)R_(10b)NCOO— nPrCO— isopropyl R_(10a)R_(10b)NCOO— nPrCO—cyclopropyl R_(10a)R_(10b)NCOO— nPrCO— cyclobutyl R_(10a)R_(10b)NCOO—nPrCO— cyclopentyl R_(10a)R_(10b)NCOO— nPrCO— phenyl R_(10a)R_(10b)NCOO—

EXAMPLE 5

[0091] Following the processes described in Example 1 and elsewhereherein, the following specific taxanes having structural formula 15 maybe prepared, wherein R₇ is hydroxy and R₁₀ in each of the series (thatis, each of series “A” through “K”) is as previously defined, includingwherein R₁₀ is R_(10a)R_(10b)NCOO— and one of R_(10a) and R_(10b) ishydrogen and the other is (i) substituted or unsubstituted C₁ to C₈alkyl such as methyl, ethyl, or straight, branched or cyclic propyl,butyl, pentyl, or hexyl; (ii) substituted or unsubstituted C₂ to C₈alkenyl such as ethenyl or straight, branched or cyclic propenyl,butenyl, pentenyl or hexenyl; (iii) substituted or unsubstituted C₂ toC₈ alkynyl such as ethynyl or straight or branched propynyl, butynyl,pentynyl, or hexynyl; (iv) phenyl or substituted phenyl such as nitro,alkoxy or halosubstituted phenyl, or (v) substituted or unsubstitutedheteroaromatic such as furyl, thienyl, or pyridyl. The substituents maybe those identified elsewhere herein for substituted hydrocarbyl. In oneembodiment, preferred R₁₀ substituents include R_(10a)R_(10b)NCOO—wherein one of R_(10a) and R_(10b) is hydrogen and the other is methyl,ethyl, or straight, branched or cyclic propyl. In another embodiment,preferred R₁₀ substituents include R_(10a)R_(10b)NCOO— wherein one ofR_(10a) and R_(10b) is hydrogen and the other is substituted methyl,ethyl, or straight, branched or cyclic propyl.

[0092] In the “A” series of compounds, X₁₀ is as otherwise as definedherein. Preferably, heterocyclo is substituted or unsubstitued furyl,thienyl, or pyridyl, X₁₀ is substituted or unsubstitued furyl, thienyl,pyridyl, phenyl, or lower alkyl (e.g., tert-butyl), and R₇ and R₁₀ eachhave the beta stereochemical configuration.

[0093] In the “B” series of compounds, X₁₀ and R_(2a) are as otherwiseas defined herein. Preferably, heterocyclo is preferably substituted orunsubstitued furyl, thienyl, or pyridyl, X₁₀ is preferably substitutedor unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl (e.g.,tert-butyl), R_(2a), is preferably substituted or unsubstitued furyl,thienyl, pyridyl, phenyl, or lower alkyl, and R₇ and R₁₀ each have thebeta stereochemical configuration.

[0094] In the “C” series of compounds, X₁₀ and R_(9a) are as otherwiseas defined herein. Preferably, heterocyclo is preferably substituted orunsubstitued furyl, thienyl, or pyridyl, X₁₀ is preferably substitutedor unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl (e.g.,tert-butyl), R_(9a) is preferably substituted or unsubstitued furyl,thienyl, pyridyl, phenyl, or lower alkyl, and R₇, R₉ and R₁₀ each havethe beta stereochemical configuration.

[0095] In the “D” and “E” series of compounds, X₁₀ is as otherwise asdefined herein. Preferably, heterocyclo is preferably substituted orunsubstitued furyl, thienyl, or pyridyl, X₁₀ is preferably substitutedor unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl (e.g.,tert-butyl), and R₇, R₉ (series D only) and R₁₀ each have the betastereochemical configuration.

[0096] In the “F” series of compounds, X₁₀, R_(2a) and R_(9a) are asotherwise as defined herein. Preferably, heterocyclo is preferablysubstituted or unsubstitued furyl, thienyl, or pyridyl, X₁₀ ispreferably substituted or unsubstitued furyl, thienyl, pyridyl, phenyl,or lower alkyl (e.g., tert-butyl), R_(2a) is preferably substituted orunsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl, and R₇, R₉and R₁₀ each have the beta stereochemical configuration.

[0097] In the “G” series of compounds, X₁₀ and R_(2a) are as otherwiseas defined herein. Preferably, heterocyclo is preferably substituted orunsubstitued furyl, thienyl, or pyridyl, X₁₀ is preferably substitutedor unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl (e.g.,tert-butyl), R_(2a) is preferably substituted or unsubstitued furyl,thienyl, pyridyl, phenyl, or lower alkyl, and R₇, R₉ and R₁₀ each havethe beta stereochemical configuration.

[0098] In the “H” series of compounds, X₁₀ is as otherwise as definedherein. Preferably, heterocyclo is preferably substituted orunsubstitued furyl, thienyl, or pyridyl, X₁₀ is preferably substitutedor unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl (e.g.,tert-butyl), R_(2a) is preferably substituted or unsubstitued furyl,thienyl, pyridyl, phenyl, or lower alkyl, and R₇ and R₁₀ each have thebeta stereochemical configuration.

[0099] In the “I” series of compounds, X₁₀ and R_(2a), are as otherwiseas defined herein. Preferably, heterocyclo is preferably substituted orunsubstitued furyl, thienyl, or pyridyl, X₁₀ is preferably substitutedor unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl (e.g.,tert-butyl), R_(2a) is preferably substituted or unsubstitued furyl,thienyl, pyridyl, phenyl, or lower alkyl, and R₇ and R₁₀ each have thebeta stereochemical configuration.

[0100] In the “J” series of compounds, X₁₀ and R_(2a), are as otherwiseas defined herein. Preferably, heterocyclo is preferably substituted orunsubstitued furyl, thienyl, or pyridyl, X₁₀ is preferably substitutedor unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl (e.g.,tert-butyl), R_(2a) is preferably substituted or unsubstitued furyl,thienyl, pyridyl, phenyl, or lower alkyl, and R₇, R₉ and R₁₀ each havethe beta stereochemical configuration.

[0101] In the “K” series of compounds, X₁₀, R_(2a) and R_(9a) are asotherwise as defined herein. Preferably, heterocyclo is preferablysubstituted or unsubstitued furyl, thienyl, or pyridyl, X₁₀ ispreferably substituted or unsubstitued furyl, thienyl, pyridyl, phenyl,or lower alkyl (e.g., tert-butyl), R_(2a) is preferably substituted orunsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl, and R₇, R₉and R₁₀ each have the beta stereochemical configuration.

[0102] Any substituents of each of X₃, X₅, R₂, R₇, and R₉ may behydrocarbyl or any of the heteroatom containing substituents selectedfrom the group consisting of heterocyclo, alkoxy, alkenoxy, alkynoxy,aryloxy, hydroxy, protected hydroxy, keto, acyloxy, nitro, amino, amido,thiol, ketal, acetal, ester and ether moieties, but not phosphorouscontaining moieties.

Series X₅ X₃ R₁₀ R₂ R₉ R₁₄ A1 —COOX₁₀ heterocyclo R_(10a)R_(10b)NCOO—C₆H₅COO— O H A2 —COX₁₀ heterocyclo R_(10a)R_(10b)NCOO— C₆H₅COO— O H A3—CONHX₁₀ heterocyclo R_(10a)R_(10b)NCOO— C₆H₅COO— O H A4 —COX₁₀optionally R_(10a)R_(10b)NCOO— C₆H₅COO— O H substituted C₂ to C₈ alkylA5 —COX₁₀ optionally R_(10a)R_(10b)NCOO— C₆H₅COO— O H substituted C₂ toC₈ alkyl A6 —CONHX₁₀ optionally R_(10a)R_(10b)NCOO— C₆H₅COO— O Hsubstituted C₂ to C₈ alkyl A7 —COOX₁₀ optionally R_(10a)R_(10b)NCOO—C₆H₅COO— O H substituted C₂ to C₈ alkenyl A8 —COX₁₀ optionallyR_(10a)R_(10b)NCOO— C₆H₅COO— O H substituted C₂ to C₈ alkenyl A9—CONHX₁₀ optionally R_(10a)R_(10b)NCOO— C₆H₅COO— O H substituted C₂ toC₈ alkenyl A10 —COOX₁₀ optionally R_(10a)R_(10b)NCOO— C₆H₅COO— O Hsubstituted C₂ to C₈ alkynyl A11 —COX₁₀ optionally R_(10a)R_(10b)NCOO—C₆H₅COO— O H substituted C₂ to C₈ alkynyl A12 —CONHX₁₀ optionallyR_(10a)R_(10b)NCOO— C₆H₅COO— O H substituted C₂ to C₈ alkynyl B1 —COOX₁₀heterocyclo R_(10b)R_(10b)NCOO— R_(2a)COO— O H B2 —COX₁₀ heterocycloR_(10a)R_(10b)NCOO— R_(2a)COO— O H B3 —CONHX₁₀ heterocycloR_(10a)R_(10b)NCOO— R_(2a)COO— O H B4 —COOX₁₀ optionallyR_(10a)R_(10b)NCOO— R_(2a)COO— O H substituted C₂ to C₈ alkyl B5 —COX₁₀optionally R_(10a)R_(10b)NCOO— R_(2a)COO— O H substituted C₂ to C₈ alkylB6 —CONHX₁₀ optionally R_(10a)R_(10b)NCOO— R_(2a)COO— O H substituted C₂to C₈ alkyl B7 —COOX₁₀ optionally R_(10a)R_(10b)NCOO— R_(2a)COO— O Hsubstituted C₂ to C₈ alkenyl B8 —COX₁₀ optionally R_(10a)R_(10b)NCOO—R_(2a)COO— O H substituted C₂ to C₈ alkenyl B9 —CONHX₁₀ optionallyR_(10a)R_(10b)NCOO— R_(2a)COO— O H substituted C₂ to C₈ alkenyl B10—COOX₁₀ optionally R_(10a)R_(10b)NOOO R_(2a)COO— O H substituted C₂ toC₈ alkynyl B11 —COX₁₀ optionally R_(10a)R_(10b)NOOO- R_(2a)COO— O Hsubstituted C₂ to C₈ alkynyl B12 —CONHX₁₀ optionally R_(10a)R_(10b)NCOO—R_(2a)COO— O H substituted C₂ to C₈ alkynyl C1 —COOX₁₀ heterocycloR_(10a)R_(10b)NCOO— C₆H₅COO— R_(9a)COO— H C2 —COX₁₀ heterocycloR_(10a)R_(10b)NCOO— C₆H₅COO— R_(9a)COO— H C3 —CONHX₁₀ heterocycloR_(10a)R_(10b)NCOO— C₆H₅COO— R_(9a)COO— H C4 —COOX₁₀ optionallyR_(10a)R_(10b)NCOO— C₆H₅COO— RgaCOO H substituted C₂ to C₈ alkyl C5—COX₁₀ optionally R_(10a)R_(10b)NCOO— C₆H₅COO— R_(9a)COO— H substitutedC₂ to C₈ alkyl C6 —CONHX₁₀ optionally R_(10a)R_(10b)NCOO— C₆H₅COO—R_(9a)COO— H substituted C₂ to C₈ alkyl C7 —COOX₁₀ optionallyR_(10a)R_(10b)NCOO— C₆H₅COO— R_(9a)COO— H substituted C₂ to C₈ alkenylC8 —COX₁₀ optionally R_(10a)R_(10b)NCOO— C₆H₅COO— R_(9a)COO— Hsubstituted C₂ to C₈ alkenyl C9 —CONHX₁₀ optionally R_(10a)R_(10b)NCOO—C₆H₅COO— R_(9a)COO— H substituted C₂ to C₈ alkenyl C10 —COOX₁₀optionally R_(10a)R_(10b)NCOO— C₆H₅COO— R_(9a)COO— H substituted C₂ toC₈ alkynyl C11 —COX₁₀ optionally R_(10a)R_(10b)NCOO— C₆H₅COO— R_(9a)COO—H substituted C₂ to C₈ alkynyl C12 —CONHX₁₀ optionallyR_(10a)R_(10b)NCOO— C₆H₅COO— R_(9a)COO— H substituted C₂ to C₈ alkynylD1 —COOX₁₀ heterocyclo R_(10a)R_(10b)NCOO— C₆H₅COO— OH H D2 —COX₁₀heterocyclo R_(10a)R_(10b)NCOO— C₆H₅COO— OH H D3 —CONHX₁₀ heterocycloR_(10a)R_(10b)NCOO— C₆H₅COO— OH H D4 —COOX₁₀ optionallyR_(10a)R_(10b)NOO- C₆H₅COO— OH H substituted C₂ to C₈ alkyl D5 —COX₁₀optionally R_(10a)R_(10b)NCOO— C₆H₅COO— OH H substituted C₂ to C₈ alkylD6 —CONHX₁₀ optionally R_(10a)R_(10b)NCOO— C₆H₅COO— OH H substituted C₂to C₈ alkyl D7 —COOX₁₀ optionally R_(10a)R_(10b)NCOO— C₆H₅COO— OH Hsubstituted C₂ to C₈ alkenyl D8 —COX₁₀ optionally R_(10a)R_(10b)NCOO—C₆H₅COO— OH H substituted C₂ to C₈ alkenyl D9 —CONHX₁₀ optionallyR_(10a)R_(10b)NCOO— C₃H₅COO— OH H substituted C₂ to C₈ alkenyl D10—COOX₁₀ optionally R_(10a)R_(10b)NCOO— C₆H₅COO— OH H substituted C₂ toC₈ alkynyl D11 —COX₁₀ optionally R_(10a)R_(10b)NCOO— C₆H₅COO— OH Hsubstituted C₂ to C₈ alkynyl D12 —CONHX₁₀ optionally R_(10a)R_(10b)NCOO—C₆H₅COO— OH H substituted C₂ to C₈ alkynyl E1 —COOX₁₀ heterocycloR_(10a)R_(10b)NCOO— C₆H₅COO— O OH E2 —COX₁₀ heterocycloR_(10a)R_(10b)NCOO— C₆H₅COO— O OH E3 —CONHX₁₀ heterocycloR_(10a)R_(10b)NCOO— C₆H₅COO— O OH E4 —COOX₁₀ optionallyR_(10a)R_(10b)NCOO— C₆H₅COO— O OH substituted C₂ to C₈ alkyl E5 —COX₁₀optionally R_(10a)R_(10b)NCOO— C₆H₅COO— O OH substituted C₂ to C₈ alkylE6 —CONHX₁₀ optionally R_(10a)R_(10b)NCOO— C₆H₅COO— O OH substituted C₂to C₈ alkyl E7 —COOX₁₀ optionally R_(10a)R_(10b)NCOO— C₆H₅COO— O OHsubstituted C₂ to C₈ alkenyl E8 —COX₁₀ optionally R_(10a)R_(10b)NCOO—C₆H₅COO— O OH substituted C₂ to C₈ alkenyl E9 —CONHX₁₀ optionallyR_(10a)R_(10b)NCOO— C₆H₅COO— O OH substituted C₂ to C₈ alkenyl E10—COOX₁₀ optionally R_(10a)R_(10b)NCOO— C₆H₅COO— O OH substituted C₂ toC₈ alkynyl E11 —COX₁₀ optionally R_(10a)R_(10b)NCOO— C₆H₅COO— O OHsubstituted C₂ to C₈ alkynyl E12 —CONHX₁₀ optionally R_(10a)R_(10b)NCOO—C₆H₅COO— O OH substituted C₂ to C₈ alkynyl F1 —COOX₁₀ heterocycloR_(10a)R_(10b)NCOO— R_(2a)COO— R_(9a)COO— H F2 —COX₁₀ heterocycloR_(10a)R_(10b)NCOO— R_(2a)COO— R_(9a)COO— H F3 —CONHX₁₀ heterocycloR_(10a)R_(10b)NCOO— R_(2a)COO— R_(9a)COO— H F4 —COOX₁₀ optionallyR_(10a)R_(10b)NCOO— R_(2a)COO— R_(9a)COO— H substituted C₂ to C₈ alkylF5 —COX₁₀ optionally R_(10a)R_(10b)NCOO— R_(2a)COO— R_(9a)COO— Hsubstituted C₂ to C₈ alkyl F6 —CONHX₁₀ optionally R_(10a)R_(10b)NCOO—R_(2a)COO— R_(9a)COO— H substituted C₂ to C₈ alkyl F7 —COOX₁₀ optionallyR_(10a)R_(10b)NCOO— R_(2a)COO— R_(9a)COO— H substituted C₂ to C₈ alkenylF8 —COX₁₀ optionally R_(10a)R_(10b)NCOO— R_(2a)COO— R_(9a)COO— Hsubstituted C₂ to C₈ alkenyl F9 —CONHX₁₀ optionally R_(10a)R_(10b)NCOO—R_(2a)COO— R_(9a)COO— H substituted C₂ to C₈ alkenyl F10 —COOX₁₀optionally R_(10a)R_(10b)NCOO— R_(2a)COO— R_(9a)COO— H substituted C₂ toC₈ alkynyl F11 —COX₁₀ optionally R_(10a)R_(10b)NCOO— R_(2a)COO—R_(9a)COO— H substituted C₂ to C₈ alkynyl F12 —CONHX₁₀ optionallyR_(10a)R_(10b)NCOO— R_(2a)COO— R_(9a)COO— H substituted C₂ to C₅ alkynylG1 —COOX₁₀ heterocyclo R_(10a)R_(10b)NCOO— R_(2a)COO— OH H G2 —COX₁₀heterocyclo R_(10a)R_(10b)NCOO— R_(2a)COO— OH H G3 —CONHX₁₀ heterocycloR_(10a)R_(10b)NCOO— R_(2a)COO— OH H G4 —COOX₁₀ optionallyR_(10a)R_(10b)NCOO— R_(2a)COO— OH H substituted C₂ to C₈ alkyl G5 —COX₁₀optionally R_(10a)R_(10b)NCOO— R_(2a)COO— OH H substituted C₂ to C₈alkyl G6 —CONHX₁₀ optionally R_(10a)R_(10b)NCOO— R_(2a)COO— OH Hsubstituted C₂ to C₈ alkyl G7 —COOX₁₀ optionally R_(10a)R_(10b)NCOO—R_(2a)COO— OH H substituted C₂ to C₈ alkenyl G8 —COX₁₀ optionallyR_(10a)R_(10b)NCOO— R_(2a)COO— OH H substituted C₂ to C₈ alkenyl G9—CONHX₁₀ optionally R_(10a)R_(10b)NCOO— R_(2a)COO— OH H substituted C₂to C₈ alkenyl G10 —COOX₁₀ optionally R_(10a)R_(10b)NCOO— R_(2a)COO— OH Hsubstituted C₂ to C₈ alkynyl G11 —COX₁₀ optionally R_(10a)R_(10b)NCOO—R_(2a)COO— OH H substituted C₂ to C₈ alkynyl G12 —CONHX₁₀ optionallyR_(10a)R_(10b)NCOO— R_(2a)COO— OH H substituted C₂ to C₈ alkynyl H1—COOX₁₀ heterocyclo R_(10a)R_(10b)NCOO— C₆H₅COO— OH OH H2 —COX₁₀heterocyclo R_(10a)R_(10b)NCOO— C₆H₅COO— OH OH H3 —CONHX₁₀ heterocycloR_(10a)R_(10b)NCOO— C₆H₅COO— OH OH H4 —COOX₁₀ optionallyR_(10a)R_(10b)NCOO— C₆H₅COO— OH OH substituted C₂ to C₈ alkyl H5 —COX₁₀optionally R_(10a)R_(10b)NCOO— C₆H₅COO— OH OH substituted C₂ to C₈ alkylH6 —CONHX₁₀ optionally R_(10a)R_(10b)NCOO— C₆H₅COO— OH OH substituted C₂to C₈ alkyl H7 —COOX₁₀ optionally R_(10a)R_(10b)NCOO— C₆H₅COO— OH OHsubstituted C₂ to C₈ alkenyl H8 —COX₁₀ optionally R_(10a)R_(10b)NCOO—C₆H₅COO— OH OH substituted C₂ to C₈ alkenyl H9 —CONHX₁₀ optionallyR_(10a)R_(10b)NCOO— C₆H₅COO— OH OH substituted C₂ to C₈ alkenyl H10—COOX₁₀ optionally R_(10a)R_(10b)NCOO— C₆H₅COO— OH OH substituted C₂ toC₈ alkynyl H11 —COX₁₀ optionally R_(10a)R_(10b)NCOO— C₆H₅COO— OH OHsubstituted C₂ to C₈ alkynyl H12 —CONHX₁₀ optionally R_(10a)R_(10b)NCOO—C₆H₅COO— OH OH substituted C₂ to C₈ alkynyl I1 —COOX₁₀ heterocycloR_(10a)R_(10b)NCOO— R_(2a)COO— O OH I2 —COX₁₀ heterocycloR_(10a)R_(10b)NCOO— R_(2a)COO— O OH I3 —CONHX₁₀ heterocycloR_(10a)R_(10b)NCOO— R_(2a)COO— O OH I4 —COOX₁₀ optionallyR_(10a)R_(10b)NCOO— R_(2a)COO— O OH substituted C₂ to C₈ alkyl I5 —COX₁₀optionally R_(10a)R_(10b)NCOO— R_(2a)COO— O OH substituted C₂ to C₈alkyl I6 —CONHX₁₀ optionally R_(10a)R_(10b)NCOO— R_(2a)COO— O OHsubstituted C₂ to C₈ alkyl I7 —COOX₁₀ optionally R_(10a)R_(10b)NCOO—R_(2a)COO— O OH substituted C₂ to C₈ alkenyl I8 —COX₁₀ optionallyR_(10a)R_(10b)NCOO— R_(2a)COO— O OH substituted C₂ to C₈ alkenyl I9—CONHX₁₀ optionally R_(10a)R_(10b)NCOO— R_(2a)COO— O OH substituted C₂to C₈ alkenyl I10 —COOX₁₀ optionally R_(10a)R_(10b)NCOO— R_(2a)COO— O OHsubstituted C₂ to C₈ alkynyl I11 —COX₁₀ optionally R_(10a)R_(10b)NCOO—R_(2a)COO— O OH substituted C₂ to C₈ alkynyl I12 —CONHX₁₀ optionallyR_(10a)R_(10b)NCOO— R_(2a)COO— O OH substituted C₂ to C₈ alkynyl J1—COOX₁₀ heterocyclo R_(10a)R_(10b)NCOO— R_(2a)COO— OH OH J2 —COX₁₀heterocyclo R_(10a)R_(10b)NCOO— R_(2a)COO— OH OH J3 —CONHX₁₀ heterocycloR_(10a)R_(10b)NCOO— R_(2a)COO— OH OH J4 —COOX₁₀ optionallyR_(10a)R_(10b)NCOO— R_(2a)COO— OH OH substituted C₂ to C₈ alkyl J5—COX₁₀ optionally R_(10a)R_(10b)NCOO— R_(2a)COO— OH OH substituted C₂ toC₈ alkyl J6 —CONHX₁₀ optionally R_(10a)R_(10b)NCOO— R_(2a)COO— OH OHsubstituted C₂ to C₈ alkyl J7 —COOX₁₀ optionally R_(10a)R_(10b)NCOO—R_(2a)COO— OH OH substituted C₂ to C₈ alkenyl J8 —COX₁₀ optionallyR_(10a)R_(10b)NCOO— R_(2a)COO— OH OH substituted C₂ to C₈ alkenyl J9—CONHX₁₀ optionally R_(10a)R_(10b)NCOO— R_(2a)COO— OH OH substituted C₂to C₈ alkenyl J10 —COOX₁₀ optionally R_(10a)R_(10b)NCOO— R_(2a)COO— OHOH substituted C₂ to C₈ alkynyl J11 —COX₁₀ optionallyR_(10a)R_(10b)NCOO— R_(2a)COO— OH OH substituted C₂ to C₈ alkynyl J12—CONHX₁₀ optionally R_(10a)R_(10b)NCOO— R_(2a)COO— OH OH substituted C₂to C₈ alkynyl K1 —COOX₁₀ heterocyclo R_(10a)R_(10b)NCOO— R_(2a)COO—R_(9a)COO— OH K2 —COX₁₀ heterocyclo R_(10a)R_(10b)NCOO— R_(2a)COO—R_(9a)COO— OH K3 —CONHX₁₀ heterocyclo R_(10a)R_(10b)NCOO— R_(2a)COO—R_(9a)COO— OH K4 —COOX₁₀ optionally R_(10a)R_(10b)NCOO— R_(2a)COO—R_(9a)COO— OH C₂ to C₈ alkyl K5 —COX₁₀ optionally R_(10a)R_(10b)NCOO—R_(2a)COO— R_(9a)COO— OH substituted C₂ to alkyl K6 —CONHX₁₀ optionallyR_(10a)R_(10b)NCOO— R_(2a)COO— R_(9a)COO— OH substituted C₂ to C₈ alkylK7 —COOX₁₀ optionally R_(10a)R_(10b)NCOO— R_(2a)COO— R_(9a)COO— OHsubstituted C₂ to C₈ alkenyl K8 —COX₁₀ optionally R_(10a)R_(10b)NCOO—R_(2a)COO— R_(9a)COO— OH substituted C₂ to C₈ alkenyl K9 —CONHX₁₀optionally R_(10a)R_(10b)NCOO— R_(2a)COO— R_(9a)COO— OH substituted C₂to C₈ alkenyl K10 —COOX₁₀ optionally R_(10a)R_(10b)NCOO— R_(2a)COO—R_(9a)COO— OH substituted C₂ to C₈ alkynyl K11 —COX₁₀ optionallyR_(10a)R_(10b)NCOO— R_(2a)COO— R_(9a)COO— OH substituted C₂ to C₈alkynyl K12 —CONHX₁₀ optionally R_(10a)R_(10b)NCOO— R_(2a)COO—R_(9a)COO— OH substituted C₂ to C₈ alkynyl

EXAMPLE 6

[0103] In Vitro cytotoxicity measured by the cell colony formation assay

[0104] Four hundred cells (HCT116) were plated in 60 mm Petri dishescontaining 2.7 mL of medium (modified McCoy's 5a medium containing 10%fetal bovine serum and 100 units/mL penicillin and 100 g/mLstreptomycin). The cells were incubated in a CO₂ incubator at 37° C. for5 h for attachment to the bottom of Petri dishes. The compoundsidentified in Example 2 were made up fresh in medium at ten times thefinal concentration, and then 0.3 mL of this stock solution was added tothe 2.7 mL of medium in the dish. The cells were then incubated withdrugs for 72 h at 37° C. At the end of incubation the drug-containingmedia were decanted, the dishes were rinsed with 4 mL of Hank's BalanceSalt Solution (HBSS), 5 mL of fresh medium was added, and the disheswere returned to the incubator for colony formation. The cell colonieswere counted using a colony counter after incubation for 7 days. Cellsurvival was calculated and the values of ID50 (the drug concentrationproducing 50% inhibition of colony formation) were determined for eachtested compound. IN VITRO Compound ID 50 (nm) HCT116 taxol 2.1 docetaxel0.6 2600 <1 2616 27 2622 <1 2633 <10 2686 <1 2692 <1 2700 <1 2717 <12722 <1 2733 <10 2757 <1 2640 <1 2743 <1 6015 <10 6024 <1 6072 <1

1. A taxane having the formula:

wherein R₂ is acyloxy; R₇ is hydroxy; R₉ is keto, hydroxy, or acyloxy;R₁₀ is carbamoyloxy; R₁₄ is hydrido or hydroxy; X₃ is substituted orunsubstituted alkyl, alkenyl, alkynyl, phenyl or heterocyclo, whereinalkyl comprises at least two carbon atoms; X₅ is —COX₁₀, —COOX₁₀, or—CONHX,₁₀; X₁₀ is hydrocarbyl, substituted hydrocarbyl, or heterocyclo;and Ac is acetyl.
 2. The taxane of claim 1 wherein R₁₀ isR_(10a)R_(10b)NCOO— and R_(10a) and R_(10b) are independently hydrogen,hydrocarbyl, substituted hydrocarbyl, or heterocyclo.
 3. The taxane ofclaim 2 wherein X₃ is 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl,3-pyridyl, 4-pyridyl, C₁-C₈ alkyl, C₂- C₈ alkenyl, or C₂- C8 alkynyl. 4.The taxane of claim 2 wherein X₅ is —COX₁₀ and X₁₀ is substituted orunsubstituted phenyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl,3-pyridyl, 4-pyridyl, C₁-C₈ alkyl, C₂-C₈ alkenyl, or C₂-C₈ alkynyl, orX₅ is —COOX₁₀ and X₁₀ is substituted or unsubstituted C₁-C₈ alkyl, C₂-C₈alkenyl, or C₂-C₈ alkynyl.
 5. The taxane of claim 2 wherein X₅ is —COX₁₀wherein X₁₀ is phenyl, or X₅ is —COOX₁₀ wherein X₁₀ is t-butyl.
 6. Thetaxane of claim 2 wherein R₁₄ is hydrido.
 7. The taxane of claim 6wherein X₃ is 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl,3-pyridyl, 4-pyridyl, C₁-C₈ alkyl, C₂-C₈ alkenyl, or C₂-C₈ alkynyl. 8.The taxane of claim 6 wherein X₅ is —COX₁₀ and X₁₀ is substituted orunsubstituted phenyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl,3-pyridyl, 4-pyridyl, C₁-C₈ alkyl, C₂-C₈ alkenyl, or C₂-C₈ alkynyl or X₅is —COOX₁₀ and X₁₀ is substituted or unsubstituted C₁-C₈ alkyl, C₂-C₈alkenyl, or C₂-C₈ alkynyl.
 9. The taxane of claim 6 wherein X₅ is —COX₁₀and X₁₀ is phenyl, or X₅ iS —COOX₁₀ and X₁₀ is t-butyl.
 10. The taxaneof claim 2 wherein R₂ is benzoyloxy.
 11. The taxane of claim 10 whereinX₃ is 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl,4-pyridyl, C₁-C₈ alkyl, C₂-C₈ alkenyl, or C₂-C₈ alkynyl.
 12. The taxaneof claim 10 wherein X₅ is —COX₁₀ and X₁₀ is substituted or unsubstitutedphenyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl,4-pyridyl, C₁-C₈ alkyl, C₂-C₈ alkenyl, or C₂-C₈ alkynyl or X₅ is —COOX₁₀and X₁₀ is substituted or unsubstituted C₁-C₈ alkyl, C₂-C₈ alkenyl, orC₂-C₈ alkynyl.
 13. The taxane of claim 10 wherein X₅ is —COX₁₀ and X₁₀is phenyl, or X₅ is —COOX₁₀ and X₁₀ is t-butyl.
 14. The taxane of claim2 wherein R₁₄ is hydrido and R₉ is keto.
 15. The taxane of claim 14wherein X₃ is 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl,3-pyridyl, 4-pyridyl, C₁-C₈ alkyl, C₂-C₈ alkenyl, or C₂-C₈ alkynyl. 16.The taxane of claim 14 wherein X₅ is —COX₁₀ and X₁₀ is substituted orunsubstituted phenyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl,3-pyridyl, 4-pyridyl, C₁-C₈ alkyl, C₂-C₈ alkenyl, or C₂-C₈ alkynyl or X₅is —-COOX₁₀ and X₁₀ is substituted or unsubstituted C₁-C₈ alkyl, C₂-C₈alkenyl, or C₂-C₈ alkynyl.
 17. The taxane of claim 14 wherein X₅ is—COX₁₀ and X₁₀ is phenyl, or X₅ is —COOX₁₀ and X₁₀ is t-butyl.
 18. Thetaxane of claim 2 wherein R₂ is benzoyloxy and R₉ is keto.
 19. Thetaxane of claim 18 wherein X₃ is 2-furyl, 3-furyl, 2-thienyl, 3-thienyl,2-pyridyl, 3-pyridyl, 4-pyridyl, C₁-C₈ alkyl, C₂-C₈ alkenyl, or C₂-C₈alkynyl.
 20. The taxane of claim 18 wherein X₅ is —COX₁₀ and X₁₀ issubstituted or unsubstituted phenyl, 2-furyl, 3-furyl, 2-thienyl,3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, C₁-C₈ alkyl, C₂-C₈ alkenyl,or C₂-C₈ alkynyl or X₅ is —COOX₁₀ and X₁₀ is substituted orunsubstituted C₁-C₈ alkyl, C₂-C₈ alkenyl, or C₂-C₈ alkynyl.
 21. Thetaxane of claim 18 wherein X₅ is —COX₁₀ and X₁₀ is phenyl, or X₅ is—COOX₁₀ and X₁₀ is t-butyl.
 22. The taxane of claim 2 wherein R₁₄ ishydrido and R₂ is benzoyloxy.
 23. The taxane of claim 22 wherein X₃ is2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl,C₁-C₈ alkyl, C₂-C₈ alkenyl, or C₂-C₈ alkynyl.
 24. The taxane of claim 22wherein X₅ is —COX₁₀ and X₁₀ is substituted or unsubstituted phenyl,2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl,C₁-C₈ alkyl, C₂-C₈ alkenyl, or C₂-C₈ alkynyl or X₅ is —COOX₁₀ and X₁₀ issubstituted or unsubstituted C₁-C₈ alkyl, C₂-C₈ alkenyl, or C₂-C₈alkynyl.
 25. The taxane of claim 22 wherein X₅ is —COX₁₀ and X₁₀ isphenyl, or X₅ is —COOX₁₀ and X₁₀ is t-butyl.
 26. The taxane of claim 2wherein R₁₄ is hydrido, R₉ is keto, and R₂ is benzoyloxy.
 27. The taxaneof claim 26 wherein X₃ is 2-furyl, 3-furyl, 2-thienyl, 3-thienyl,2-pyridyl, 3-pyridyl, 4-pyridyl, C₁-C₈ alkyl, C₂-C₈ alkenyl, or C₂-C₈alkynyl.
 28. The taxane of claim 26 wherein X₅ is —COX₁₀ and X₁₀ issubstituted or unsubstituted phenyl, 2-furyl, 3-furyl, 2-thienyl,3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, C₁-C₈ alkyl, C₂-C₈ alkenyl,or C₂-C₈ alkynyl or X₅ is —COOX₁₀ and X₁₀ is substituted orunsubstituted C₁-C₈ alkyl, C₂-C₈ alkenyl, or C₂-C₈ alkynyl.
 29. Thetaxane of claim 26 wherein X₅ is —COX₁₀ and X₁₀ is phenyl, or X₅ is—COOX₁₀ and X₁₀ is t-butyl.
 30. The taxane of claim 1 wherein R₁₀ isR_(10a)R_(10b)NCOO—, one of R_(10a) and R_(10b) is hydrogen and theother is hydrocarbyl, substituted hydrocarbyl, or heterocyclo.
 31. Thetaxane of claim 30 wherein X₃ is 2-furyl, 3-furyl, 2-thienyl, 3-thienyl,2-pyridyl, 3-pyridyl, 4-pyridyl, C₁-C₈ alkyl, C₂-C₈ alkenyl, or C₂-C₈alkynyl.
 32. The taxane of claim 30 wherein X₅ is —COX₁₀ and X₁₀ issubstituted or unsubstituted phenyl, 2-furyl, 3-furyl, 2-thienyl,3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, C₁-C₈ alkyl, C₂-C₈ alkenyl,or C₂-C₈ alkynyl, or X₅ is —COOX₁₀ and X₁₀ is substituted orunsubstituted C₁-C₈ alkyl, C₂-C₈ alkenyl, or C₂-C₈ alkynyl.
 33. Thetaxane of claim 30 wherein X₅ is —COX₁₀ and X₁₀ is phenyl, or X₅ is—COOX₁₀ and X₁₀ is t-butyl.
 34. The taxane of claim 30 wherein R₁₄ ishydrido.
 35. The taxane of claim 34 wherein X₃ is 2-furyl, 3-furyl,2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, C₁-C₈ alkyl,C₂-C₈ alkenyl, or C₂-C₈ alkynyl.
 36. The taxane of claim 34 wherein X₅is —COX₁₀ and X₁₀ is substituted or unsubstituted phenyl, 2-furyl,3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, C₁-C₈alkyl, C₂-C₈ alkenyl, or C₂-C₈ alkynyl or X₅ is —COOX₁₀ and X₁₀ issubstituted or unsubstituted C₁-C₈ alkyl, C₂-C₈ alkenyl, or C₂-C₈alkynyl.
 37. The taxane of claim 34 wherein X₅ is —COX₁₀ and X₁₀ isphenyl, or X₅ is —COOX₁₀ and X₁₀ is t-butyl.
 38. The taxane of claim 30wherein R₂ is benzoyloxy.
 39. The taxane of claim 38 wherein X₃ is2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl,C₁-C₈ alkyl, C₂-C₈ alkenyl, or C₂-C₈ alkynyl.
 40. The taxane of claim 38wherein X₅ is —COX₁₀ and X₁₀ is substituted or unsubstituted phenyl,2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl,C₁-C₈ alkyl, C₂-C₈ alkenyl, or C₂-C₈ alkynyl or X₅ is —COOX₁₀ and X₁₀ issubstituted or unsubstituted C₁-C₈ alkyl, C₂-C₈ alkenyl, or C₂-C₈alkynyl.
 41. The taxane of claim 38 wherein X₅ is —COX₁₀ and X₁₀ isphenyl, or X₅ is —COOX₁₀ and X₁₀ is t-butyl.
 42. The taxane of claim 30wherein R₁₄ is hydrido and R₉ is keto.
 43. The taxane of claim 42wherein X₃ is 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl,3-pyridyl, 4-pyridyl, C₁-C₈ alkyl, C₂-C₈ alkenyl, or C₂-C₈ alkynyl. 44.The taxane of claim 42 wherein X₅ is —COX₁₀ and X₁₀ is substituted orunsubstituted phenyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl,3-pyridyl, 4-pyridyl, C₁-C₈ alkyl, C₂-C₈ alkenyl, or C₂-C₈ alkynyl or X₅is —COOX₁₀ and X₁₀ is substituted or unsubstituted C₁-C₈ alkyl, C₂-C₈alkenyl, or C₂-C₈ alkynyl.
 45. The taxane of claim 42 wherein X₅ is—COX₁₀ and X₁₀ is phenyl, or X₅ is —COOX₁₀ and X₁₀ is t-butyl.
 46. Thetaxane of claim 30 wherein R₂ is benzoyloxy and R₉ is keto.
 47. Thetaxane of claim 46 wherein X₃ is 2-furyl, 3-furyl, 2-thienyl, 3-thienyl,2-pyridyl, 3-pyridyl, 4-pyridyl, C₁-C₈ alkyl, C₂-C₈ alkenyl, or C₂-C₈alkynyl.
 48. The taxane of claim 46 wherein X₅ is —COX₁₀ and X₁₀ issubstituted or unsubstituted phenyl, 2-furyl, 3-furyl, 2-thienyl,3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, C₁-C₈ alkyl, C₂-C₈ alkenyl,or C₂-C₈ alkynyl or X₅ is —COOX₁₀ and X₁₀ is substituted orunsubstituted C₁-C₈ alkyl, C₂-C₈ alkenyl, or C₂-C₈ alkynyl.
 49. Thetaxane of claim 46 wherein X₅ is —COX₁₀ and X₁₀ is phenyl, or X₅ is—COOX₁₀ and X₁₀ is t-butyl.
 50. The taxane of claim 30 wherein R₁₄ ishydrido and R₂ is benzoyloxy.
 51. The taxane of claim 50 wherein X₃ is2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl,C₁-C₈ alkyl, C₂-C₈ alkenyl, or C₂-C₈ alkynyl.
 52. The taxane of claim 50wherein X₅ is —COX₁₀ and X₁₀ is substituted or unsubstituted phenyl,2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl,C₁-C₈ alkyl, C₂-C₈ alkenyl, or C₂-C₈ alkynyl or X₅ is —COOX₁₀ and X₁₀ issubstituted or unsubstituted C₁-C₈ alkyl, C₂-C₈ alkenyl, or C₂-C₈alkynyl.
 53. The taxane of claim 50 wherein X₅ is —COX₁₀ and X₁₀ isphenyl, or X₅ is —COOX₁₀ and X₁₀ is t-butyl.
 54. The taxane of claim 30wherein R₁₄ is hydrido, R₉ is keto, and R₂ is benzoyloxy.
 55. The taxaneof claim 54 wherein X₃ is 2-furyl, 3-furyl, 2-thienyl, 3-thienyl,2-pyridyl, 3-pyridyl, 4-pyridyl, C₁-C₈ alkyl, C₂-C₈ alkenyl, or C₂-C₈alkynyl.
 56. The taxane of claim 54 wherein X₅ is —COX₁₀ and X₁₀ issubstituted or unsubstituted phenyl, 2-furyl, 3-furyl, 2-thienyl,3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, C₁-C₈ alkyl, C_(w)-C₈alkenyl, or C₂-C₈ alkynyl or X₅ is —COOX₁₀ and X₁₀ is substituted orunsubstituted C₁-C₈ alkyl, C₂-C₈ alkenyl, or C₂-C₈ alkynyl.
 57. Thetaxane of claim 54 wherein X₅ is —COX₁₀ and X₁₀ is phenyl, or X₅ is—COOX₁₀ and X₁₀ is t-butyl.
 58. The taxane of claim 1 wherein R₁₀ isR_(10a)R_(10b)NCOO—, one of R_(10a) and R_(10b) is hydrogen and theother is substituted or unsubstituted C₁-C₈ alkyl, phenyl, furyl,thienyl or pyridyl.
 59. The taxane of claim 58 wherein X₃ is 2-furyl,3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, C₁-C₈alkyl, C₂-C₈ alkenyl, or C₂-C₈ alkynyl.
 60. The taxane of claim 58wherein X₅ is —COX₁₀ and X₁₀ is substituted or unsubstituted phenyl,2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl,C₁-C₈ alkyl, C₂-C₈ alkenyl, or C₂-C₈ alkynyl, or X₅ is —COOX₁₀ and X₁₀is substituted or unsubstituted C₁-C₈ alkyl, C₂-C₈ alkenyl, or C₂-C₈alkynyl.
 61. The taxane of claim 58 wherein X₅ is —COX₁₀ and X₁₀ isphenyl, or X₅ is —COOX₁₀ and X₁₀ is t-butyl.
 62. The taxane of claim 58wherein R₁₄ is hydrido.
 63. The taxane of claim 62 wherein X₃ is2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl,C₁-C₈ alkyl, C₂-C₈ alkenyl, or C₂-C₈ alkynyl.
 64. The taxane of claim 62wherein X₅ is —COX₁₀ and X₁₀ is substituted or unsubstituted phenyl,2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl,C₁-C₈ alkyl, C₂-C₈ alkenyl, or C₂-C₈ alkynyl or X₅ is —COOX₁₀ and X₁₀ issubstituted or unsubstituted C₁-C₈ alkyl, C₂-C₈ alkenyl, or C₂-C₈alkynyl.
 65. The taxane of claim 62 wherein X₅ is —COX₁₀ and X₁₀ isphenyl, or X₅ is —COOX₁₀ and X₁₀ is t-butyl.
 66. The taxane of claim 58wherein R₂ is benzoyloxy.
 67. The taxane of claim 66 wherein X₃ is2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl,C₁-C₈ alkyl, C₂-C₈ alkenyl, or C₂-C₈ alkynyl.
 68. The taxane of claim 66wherein X₅ is —COX₁₀ and X₁₀ is substituted or unsubstituted phenyl,2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl,C₁-C₈ alkyl, C₂-C₈ alkenyl, or C₂-C₈ alkynyl or X₅ is —COOX₁₀ and X₁₀ issubstituted or unsubstituted C₁-C₈ alkyl, C₂-C₈ alkenyl, or C₂-C₈alkynyl.
 69. The taxane of claim 66 wherein X₅ is —COX₁₀ and X₁₀ isphenyl, or X₅ is —COOX₁₀ and X₁₀ is t-butyl.
 70. The taxane of claim 58wherein R₁₄ is hydrido and R₉ is keto.
 71. The taxane of claim 70wherein X₃ is 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl,3-pyridyl, 4-pyridyl, C₁-C₈ alkyl, C₂-C₈ alkenyl, or C₂-C₈ alkynyl. 72.The taxane of claim 70 wherein X₅ is —COX₁₀ and X₁₀ is substituted orunsubstituted phenyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl,3-pyridyl, 4-pyridyl, C₁-C₈ alkyl, C₂-C₈ alkenyl, or C₂-C₈ alkynyl or X₅is —COOX₁₀ and X₁₀ is substituted or unsubstituted C₁-C₈ alkyl, C₂-C₈alkenyl, or C₂-C₈ alkynyl.
 73. The taxane of claim 70 wherein X₅ is—COX₁₀ and X₁₀ is phenyl, or X₅ is —COOX₁₀ and X₁₀ is t-butyl.
 74. Thetaxane of claim 58 wherein R₂ is benzoyloxy and R₉ is keto.
 75. Thetaxane of claim 74 wherein X₃ is 2-furyl, 3-furyl, 2-thienyl, 3-thienyl,2-pyridyl, 3-pyridyl, 4-pyridyl, C₁-C₈ alkyl, C₂-C₈ alkenyl, or C₂-C₈alkynyl.
 76. The taxane of claim 74 wherein X₅ is —COX₁₀ and X₁₀ issubstituted or unsubstituted phenyl, 2-furyl, 3-furyl, 2-thienyl,3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, C₁-C₈ alkyl, C₂-C₈ alkenyl,or C₂-C₈ alkynyl or X₅ is —COOX₁₀ and X₁₀ is substituted orunsubstituted C₁-C₈ alkyl, C₂-C₈ alkenyl, or C₂-C₈ alkynyl.
 77. Thetaxane of claim 74 wherein X₅ is —COX₁₀ and X₁₀ is phenyl, or X₅ is—COOX₁₀ and X₁₀ is t-butyl.
 78. The taxane of claim 58 wherein R₁₄ ishydrido and R₂ is benzoyloxy.
 79. The taxane of claim 78 wherein X3 is2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl,C₁-C₈ alkyl, C₂-C₈ alkenyl, or C₂-C₈ alkynyl.
 80. The taxane of claim 78wherein X₅ is —COX₁₀ and X₁₀ is substituted or unsubstituted phenyl,2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl,C₁-C₈ alkyl, C₂-C₈ alkenyl, or C₂-C₈ alkynyl or X₅ is —COOX₁₀ and X₁₀ issubstituted or unsubstituted C₁-C₈ alkyl, C₂-C₈ alkenyl, or C₂-C₈alkynyl.
 81. The taxane of claim 78 wherein X, is —COX₁₀ and X₁₀ isphenyl, or X₅ is —COOX₁₀ and X₁₀ is t-butyl.
 82. The taxane of claim 58wherein R₁₄ is hydrido, R₉ is keto, and R₂ is benzoyloxy.
 83. The taxaneof claim 82 wherein X₃ is 2-furyl, 3-furyl, 2-thienyl, 3-thienyl,2-pyridyl, 3-pyridyl, 4-pyridyl, C₁-C₈ alkyl, C₂-C₈ alkenyl, or C₂-C₈alkynyl.
 84. The taxane of claim 82 wherein X5 is —COX₁₀ and X₁₀ issubstituted or unsubstituted phenyl, 2-furyl, 3-furyl, 2-thienyl,3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, C₁-C₈ alkyl, C₂-C₈ alkenyl,or C_(w)-C₈ alkynyl or X₅ is —COOX₁₀ and X₁₀ is substituted orunsubstituted C₁-C₈ alkyl, C₂-C₈ alkenyl, or C₂-C₈ alkynyl.
 85. Thetaxane of claim 82 wherein X₅ is —COX₁₀ and X₁₀ is phenyl, or X₅ is—COOX₁₀ and X₁₀ is t-butyl.
 86. The taxane of claim 82 wherein X₅ is—COOX₁₀ and X₁₀ is t-butyl.
 87. The taxane of claim 86 wherein X₃ is2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl,C₁-C₈ alkyl, C₂-C₈ alkenyl, or C₂-C₈ alkynyl.
 88. The taxane of claim 86wherein X₃ is furyl or thienyl.
 89. The taxane of claim 86 wherein X₃ is2-furyl.
 90. The taxane of claim 86 wherein X₃ is 2-thienyl.
 91. Thetaxane of claim 86 wherein X₃ is cycloalkyl.
 92. A taxane having theformula:

R₇ is hydroxy; R₁₀ is carbamoyloxy; X₃ is substituted or unsubstitutedalkyl, alkenyl, alkynyl, or heterocyclo, wherein alkyl comprises atleast two carbon atoms; X₅ is —COX₁₀, —COOX₁₀, or —CONHX₁₀; X₁₀ ishydrocarbyl, substituted hydrocarbyl, or heterocyclo, Ac is acetyl, andBz is benzoyl.
 93. The taxane of claim 92 wherein X₃ is 2-furyl,3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, C₁-C₈alkyl, C₂-C₈ alkenyl, or C₂-C₈ alkynyl.
 94. The taxane of claim 93wherein X₅ is —COX₁₀ and X₁₀ is substituted or unsubstituted phenyl,2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl,C₁-C₈ alkyl, C₂-C₈ alkenyl, or C₂-C₈ alkynyl, or X₅ is —COOX₁₀ and X₁₀is substituted or unsubstituted C₁-C₈ alkyl, C₂-C₈ alkenyl, or C₂-C₈alkynyl.
 95. The taxane of claim 93 wherein X₅ is —COX₁₀ and X₁₀ isphenyl, or X₅ is —COOX₁₀ and X₁₀ is t-butyl.
 96. The taxane of claim 92wherein X₃ is furyl or thienyl.
 97. The taxane of claim 96 wherein X₅ is—COX₁₀ and X₁₀ is substituted or unsubstituted phenyl, 2-furyl, 3-furyl,2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, C₁-C₈ alkyl,C₂-C₈ alkenyl, or C₂-C₈ alkynyl, or X₅ is —COOX₁₀ and X₁₀ is substitutedor unsubstituted C₁-C₈ alkyl, C₂-C₈ alkenyl, or C₂-C₈ alkynyl.
 98. Thetaxane of claim 96 wherein X₅ is —COX₁₀ and X₁₀ is phenyl, or X₅ is—COOX₁₀ and X₁₀ is t-butyl.
 99. The taxane of claim 93 wherein X₃ iscycloalkyl.
 100. The taxane of claim 99 wherein X₅ is —COX₁₀ and X₁₀ issubstituted or unsubstituted phenyl, 2-furyl, 3-furyl, 2-thienyl,3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, C₁-C₈ alkyl, C₂-C₈ alkenyl,or C₂-C₈ alkynyl, or X₅ is —COOX₁₀ and X₁₀ is substituted orunsubstituted C₁-C₈ alkyl, C₂-C₈ alkenyl, or C₂-C₈ alkynyl.
 101. Thetaxane of claim 99 wherein X₅ is —COX₁₀ and X₁₀ is phenyl, or X₅ is—COOX₁₀ and X₁₀ is t-butyl.
 102. The taxane of claim 93 wherein X₃ isisobutenyl.
 103. The taxane of claim 102 wherein X₅ is —COX₁₀ and X₁₀ issubstituted or unsubstituted phenyl, 2-furyl, 3-furyl, 2-thienyl,3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, C₁-C₈ alkyl, C₂-C₈ alkenyl,or C₂-C₈ alkynyl, or X₅ is —COOX₁₀ and X₁₀ is substituted orunsubstituted C₁-C₈ alkyl, C₂-C₈ alkenyl, or C₂-C₈ alkynyl.
 104. Thetaxane of claim 102 wherein X₅ is —COX₁₀ and X₁₀ is phenyl, or X₅ is—COOX₁₀ and X₁₀ is t-butyl.
 105. The taxane of claim 92 wherein R₁₀ isR_(10a)R_(10b)NCOO—, one of R_(10a) and R_(10b) is hydrogen and theother is C₁-C₈ alkyl, phenyl or heterocyclo.
 106. The taxane of claim105 wherein X₃ is 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl,3-pyridyl, 4-pyridyl, C₁-C₈ alkyl, C₂-C₈ alkenyl, or C₂-C₈ alkynyl. 107.The taxane of claim 106 wherein X₅ is —COX₁₀ and X₁₀ is substituted orunsubstituted phenyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl,3-pyridyl, 4-pyridyl, C₁-C₈ alkyl, C₂-C₈ alkenyl, or C₂-C₈ alkynyl, orX₅ is —COOX₁₀ and X₁₀ is substituted or unsubstituted C₁-C₈ alkyl, C₂-C₈alkenyl, or C₂-C₈ alkynyl.
 108. The taxane of claim 106 wherein X₅ is—COX₁₀ and X₁₀ is phenyl, or X₅ is —COOX₁₀ and X₁₀ is t-butyl.
 109. Thetaxane of claim 105 wherein X₃ is furyl or thienyl.
 110. The taxane ofclaim 109 wherein X₅ is —COX₁₀ and X₁₀ is substituted or unsubstitutedphenyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl,4-pyridyl, C₁-C₈ alkyl, C₂-C₈ alkenyl, or C₂-C₈ alkynyl, or X₅ is—COOX₁₀ and X₁₀ is substituted or unsubstituted C₁-C₈ alkyl, C₂-C₈alkenyl, or C₂-C₈ alkynyl.
 111. The taxane of claim 109 wherein X₅ is—COX₁₀ and X₁₀ is phenyl, or X₅ is —COOX₁₀ and X₁₀ is t-butyl.
 112. Thetaxane of claim 105 wherein X₃ is cycloalkyl.
 113. The taxane of claim112 wherein X₅ is —COX₁₀ and X₁₀ is substituted or unsubstituted phenyl,2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl,C₁-C₈ alkyl, C₂-C₈ alkenyl, or C₂-C₈ alkynyl, or X₅ is —COOX₁₀ and X₁₀is substituted or unsubstituted C₁-C₈ alkyl, C₂-C₈ alkenyl, or C₂-C₈alkynyl.
 114. The taxane of claim 112 wherein X₅ is —COX₁₀ and X₁₀ isphenyl, or X₅ is —COOX₁₀ and X₁₀ is t-butyl.
 115. The taxane of claim105 wherein X₃ is isobutenyl.
 116. The taxane of claim 115 wherein X₅ is—COX₁₀ and X₁₀ is substituted or unsubstituted phenyl, 2-furyl, 3-furyl,2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, C₁-C₈ alkyl,C₂-C₈ alkenyl, or C₂-C₈ alkynyl, or X₅ is —COOX₁₀ and X₁₀ is substitutedor unsubstituted C₁-C₈ alkyl, C₂-C₈ alkenyl, or C₂-C₈ alkynyl.
 117. Thetaxane of claim 115 wherein X₅ is —COX₁₀ and X₁₀ is phenyl, or X₅ is—COOX₁₀ and X₁₀ is t-butyl.
 118. The taxane of claim 92 wherein X₃ isfuryl or thienyl, R₁₀ is R_(10a)R_(10b)NCOO—, one of R_(10a) and R_(10b)is hydrogen, the other of R_(10a) and R_(10b) is C₁-C₈ alkyl, phenyl, orheterocyclo, and X₅ is —COX₁₀ wherein X₁₀ is phenyl, or X₅ is —COOX₁₀wherein X₁₀ is t-butyl.
 119. The taxane of claim 92 wherein X₃ issubstituted or unsubstituted furyl, R₁₀ is R_(10a)R_(10b)NCOO—, one ofR_(10a) and R_(10b) is hydrogen, the other of R_(10a) and R_(10b) ismethyl, ethyl, or straight, branched or cyclic propyl, and X₅ is —COX₁₀wherein X₁₀ is phenyl, or X₅ is —COOX₁₀ wherein X₁₀ is t-butyl.
 120. Thetaxane of claim 92 wherein X₃ is substituted or unsubstituted furyl, R₁₀is R_(10a)R_(10b)NCOO—, one of R_(10a) and R_(10b) is hydrogen, theother of R_(10a) and R_(10b) is substituted or unsubstituted phenyl orheterocyclo, and X₅ is —COX₁₀ wherein X₁₀ is phenyl, or X₅ is —COOX₁₀wherein X₁₀ is t-butyl.
 121. The taxane of claim 92 wherein X₃ issubstituted or unsubstituted thienyl, one of R_(10a) and R_(10b) ishydrogen, the other of R_(10a) and R_(10b) is methyl, ethyl, orstraight, branched or cyclic propyl, and X₅ is —COX₁₀ wherein X₁₀ isphenyl, or X₅ is —COOX₁₀ wherein X₁₀ is t-butyl.
 122. The taxane ofclaim 92 wherein X₃ is substituted or unsubstituted thienyl, R₁₀ isR_(10a)R_(10b)NCOO— one of R_(10a) and R_(10b) is hydrogen, the other ofR_(10a) and R_(10b) is substituted or unsubstituted phenyl orheterocyclo, and X₅ is —COX₁₀ wherein X₁₀ is phenyl, or X₅ is —COOX₁₀wherein X₁₀ is t-butyl.
 123. The taxane of claim 92 wherein X₃ issubstituted or unsubstituted phenyl, R₁₀ is R_(10a)R_(10b)NCOO—, one ofR_(10a) and R_(10b) is hydrogen, the other of R_(10a) and R_(10b) ismethyl, ethyl, or straight, branched or cyclic propyl, and X₅ is —COX₁₀wherein X₁₀ is phenyl, or X₅ is —COOX₁₀ wherein X₁₀ is t-butyl.
 124. Thetaxane of claim 92 wherein X₃ is substituted or unsubstituted phenyl,R₁₀ is R_(10a)R_(10b)NCOO—, one of R_(10a) and R_(10b) is hydrogen, theother of R_(10a) and R_(10b) is substituted or unsubstituted phenyl orheterocyclo, and X₅ is —COX₁₀ wherein X₁₀ is phenyl, or X₅ is —COOX₁₀wherein X₁₀ is t-butyl.
 125. The taxane of claim 92 wherein X₃ isisobutenyl, one of R_(10a) and R_(10b) is hydrogen, R₁₀ isR_(10a)R_(10b)NCOO—, the other of R_(10a) and R_(10b) is methyl, ethyl,or straight, branched or cyclic propyl, and X₅ is —COX₁₀ wherein X₁₀ isphenyl, or X₅ is —COOX₁₀ wherein X₁₀ is t-butyl.
 126. The taxane ofclaim 92 wherein X₃ is alkyl, R₁₀ is R_(10a)R_(10b)NCOO—, one of R_(10a)and R_(10b) is hydrogen, the other of R_(10a) and R_(10b) is methyl,ethyl, or straight, branched or cyclic propyl, and X₅ is —COX₁₀ whereinX₁₀ is phenyl, or X₅ is —COOX₁₀ wherein X₁₀ is t-butyl.
 127. The taxaneof claim 92 wherein X₃ is 2-furyl or 2-thienyl, R₁₀ isR_(10a)R_(10b)NCOO—, one of R_(10a) and R_(10b) is hydrogen, the otherof R₁₀a and R_(10b) is methyl, ethyl, or straight, branched or cyclicpropyl, X₅ is —COOX₁₀ and X₁₀ is t-butyl.
 128. The taxane of claim 92wherein X₃ is 2-furyl or 2-thienyl, R₁₀ is R_(10a)R_(10b)NCOO—, one ofR_(10a) and R_(10b) is hydrogen, the other of R_(10a) and R_(10b) issubstituted or unsubstituted phenyl or heterocyclo, X₅ is —COOX₁₀ andX₁₀ is t-butyl.
 129. The taxane of claim 92 wherein X₃ is cycloalkyl,R₁₀ is R_(10a)R_(10b)NCOO—, one of R_(10a) and R_(10b) is hydrogen, theother of R_(10a) and R_(10b) is substituted or unsubstituted phenyl orheterocyclo, X₅ is —COOX₁₀ and X₁₀ is t-butyl.
 130. A pharmaceuticalcomposition comprising the taxane of claim 1 and at least onepharmaceutically acceptable carrier.
 131. The pharmaceutical compositionof claim 130 wherein X₃ is 2-furyl, 3-furyl, 2-thienyl, 3-thienyl,2-pyridyl, 3-pyridyl, 4-pyridyl, C₁-C₈ alkyl, C₂-C₈ alkenyl, or C₂-C₈alkynyl.
 132. The pharmaceutical composition of claim 131 wherein X₅ is—COX₁₀ and X₁₀ is substituted or unsubstituted phenyl, 2-furyl, 3-furyl,2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, C₁-C₈ alkyl,C₂-C₈ alkenyl, or C₂-C₈ alkynyl, or X₅ is —COOX₁₀ and X₁₀ is substitutedor unsubstituted C₁-C₈ alkyl, C₂-C₈ alkenyl, or C₂-C₈ alkynyl.
 133. Thepharmaceutical composition of claim 131 wherein X₅ is —COX₁₀ and X₁₀ isphenyl, or X₅ is —COOX₁₀ and X₁₀ is t-butyl.
 134. The pharmaceuticalcomposition of claim 130 wherein R₁₀ is R_(10a)R_(10b)NCOO—, one ofR_(10a) and R_(10b) is hydrogen, the other of R_(10a) and R_(10b) issubstituted or unsubstituted C₁-C₈ alkyl, phenyl or heterocyclo. 135.The pharmaceutical composition of claim 134 wherein X₃ is 2-furyl,3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, C₁-C₈alkyl, C₂-C₈ alkenyl, or C₂-C₈ alkynyl.
 136. The pharmaceuticalcomposition of claim 135 wherein X₅ is —COX₁₀ and X₁₀ is substituted orunsubstituted phenyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl,3-pyridyl, 4-pyridyl, C₁-C₈ alkyl, C₂-C₈ alkenyl, or C₂-C₈ alkynyl, orX₅ is —COOX₁₀ and X₁₀ is substituted or unsubstituted C₁-C₈ alkyl, C₂-C₈alkenyl, or C₂-C₈ alkynyl.
 137. The pharmaceutical composition of claim135 wherein X₅ is —COX₁₀ and X₁₀ is phenyl, or X₅ is —COOX₁₀ and X₁₀ ist-butyl.
 138. The pharmaceutical composition of claim 131 wherein X₃ isfuryl or thienyl, R₁₀ is R_(10a)R_(10b)NCOO—, one of R_(10a) and R_(10b)is hydrogen, the other of R_(10a) and R_(10b) is C₁-C₈ alkyl, phenyl orheterocyclo, and X₅ is —COX₁₀ and X₁₀ is phenyl, or X₅ is —COOX₁₀ andX₁₀ is t-butyl.
 139. The pharmaceutical composition of claim 131 whereinX₃ is cycloalkyl, R₁₀ is R_(10a)R_(10b)NCOO—, one of R_(10a) and R_(10b)is hydrogen, the other of R_(10a) and R_(10b) is C₁-C₈ alkyl, phenyl orheterocyclo, and X₅ is —COX₁₀ wherein X₁₀ is phenyl, or X₅ is —COOX₁₀wherein X₁₀ is t-butyl.
 140. The pharmaceutical composition of claim 131wherein X₃ is substituted or unsubstituted phenyl, R₁₀ is R_(10a)R_(10b)NCOO—, one of R_(10a) and R_(10b) is hydrogen, the other of R_(10a) andR_(10b) is C₁-C₈ alkyl, phenyl or heterocyclo, and X₅ is —COX₁₀ whereinX₁₀ is phenyl, or X₅ is —COOX₁₀ wherein X₁₀ is t-butyl.
 141. Thepharmaceutical composition of claim 131 wherein X₃ is isobutenyl, R₁₀ isR_(10a)R_(10b)NCOO—, one of R_(10a) and R_(10b) is hydrogen, the otherof R_(10a) and R_(10b) is C₁-C₈ alkyl, phenyl or heterocyclo, and X₅ is—COX₁₀ wherein X₁₀ is phenyl, or X₅ is —COOX₁₀.
 142. The pharmaceuticalcomposition of claim 131 wherein X₃ is alkyl, R₁₀ isR_(10a)R_(10b)NCOO—, one of R_(10a) and R_(10b) is hydrogen, the otherof R_(10a) and R_(10b) is C₁-C₈ alkyl, phenyl or heterocyclo, and X₅ is—COX₁₀ wherein X₁₀ is phenyl, or X₅ is —COOX₁₀ wherein X₁₀ is t-butyl.143. A pharmaceutical composition comprising the taxane of claim 92 andat least one pharmaceutically acceptable carrier.
 144. A pharmaceuticalcomposition comprising the taxane of claim 96 and at least onepharmaceutically acceptable carrier.
 145. A composition for oraladministration comprising the taxane of claim 1 and at least onepharmaceutically acceptable carrier.
 146. The composition of claim 145wherein X₃ is 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl,3-pyridyl, 4-pyridyl, C₁-C₈ alkyl, C₂-C₈ alkenyl, or C₂-C₈ alkynyl. 147.The composition of claim 146 wherein X₅ is —COX₁₀ and X₁₀ is substitutedor unsubstituted phenyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl,2-pyridyl, 3-pyridyl, 4-pyridyl, C₁-C₈ alkyl, C₂-C₈ alkenyl, or C₂-C₈alkynyl, or X₅ is —COOX₁₀ and X₁₀ is substituted or unsubstituted C₁-C₈alkyl, C₂-C₈ alkenyl, or C₂-C₈ alkynyl.
 148. The composition of claim146 wherein X₅ is —COX₁₀ and X₁₀ is phenyl, or X₅ is —COOX₁₀ and X₁₀ ist-butyl.
 149. The composition of claim 145 wherein R₁₀ isR_(10a)R_(10b)NCOO—, one of R_(10a) and R_(10b) is hydrogen, the otherof R_(10a) and R_(10b) is substituted or unsubstituted C₁-C₈ alkyl,phenyl or heterocyclo.
 150. The composition of claim 149 wherein X₃ is2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl,C₁-C₈ alkyl, C₂-C₈ alkenyl, or C₂-C₈ alkynyl.
 151. The composition ofclaim 150 wherein X₅ is —COX₁₀ and X₁₀ is substituted or unsubstitutedphenyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl,4-pyridyl, C₁-C₈ alkyl, C₂-C₈ alkenyl, or C₂-C₈ alkynyl, or X₅ is—COOX₁₀ and X₁₀ is substituted or unsubstituted C₁-C₈ alkyl, C₂-C₈alkenyl, or C₂-C₈ alkynyl.
 152. The composition of claim 150 wherein X₅is —COX₁₀ and X₁₀ is phenyl, or X₅ is —COOX₁₀ and X₁₀ is t-butyl.
 153. Acomposition for oral administration comprising the taxane of claim 92and at least one pharmaceutically acceptable carrier.
 154. A compositionfor oral administration comprising the taxane of claim 96 and at leastone pharmaceutically acceptable carrier.
 155. A method of inhibitingtumor growth in a mammal, said method comprising orally administering atherapeutically effective amount of a pharmaceutical compositioncomprising the taxane of claim 1 and at least one pharmaceuticallyacceptable carrier.
 156. The method of claim 155 wherein X₃ is 2-furyl,3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, C₁-C₈alkyl, C₂-C₈ alkenyl, or C₂-C₈ alkynyl.
 157. The method of claim 156wherein X₅ is —COX₁₀ and X₁₀ is substituted or unsubstituted phenyl,2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl,C₁-C₈ alkyl, C₂-C₈ alkenyl, or C₂-C₈ alkynyl, or X₅ is —COOX₁₀ and X₁₀is substituted or unsubstituted C₁-C₈ alkyl, C₂-C₈ alkenyl, or C₂-C₈alkynyl.
 158. The method of claim 156 wherein X₅ is —COX₁₀ and X₁₀ isphenyl, or X₅ is —COOX₁₀ and X₁₀ is t-butyl.
 159. The method of claim155 wherein R₁₀ is R_(10a)R_(10b)NCOO—, one of R_(10a) and R_(10b) ishydrogen, the other of R_(10a) and R_(10b) is substituted orunsubstituted C₁-C₈ alkyl, phenyl or heterocyclo.
 160. The method ofclaim 159 wherein X₃ is 2-furyl, 3-furyl, 2-thienyl, 3-thienyl,2-pyridyl, 3-pyridyl, 4-pyridyl, C₁-C₈ alkyl, C₂-C₈ alkenyl, or C₂-C₈alkynyl.
 161. The method of claim 160 wherein X₅ is —COX₁₀ and X₁₀ issubstituted or unsubstituted phenyl, 2-furyl, 3-furyl, 2-thienyl,3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, C₁-C₈ alkyl, C₂-C₈ alkenyl,or C₂-C₈ alkynyl, or X₅ is —COOX₁₀ and X₁₀ is substituted orunsubstituted C₁-C₈ alkyl, C₂-C₈ alkenyl, or C₂-C₈ alkynyl.
 162. Themethod of claim 160 wherein X₅ is —COX₁₀ and X₁₀ is phenyl, or X₅ is—COOX₁₀ and X₁₀ is t-butyl.
 163. A method of inhibiting tumor growth ina mammal, said method comprising orally administering a therapeuticallyeffective amount of a pharmaceutical composition comprising the taxaneof claim 92 and at least one pharmaceutically acceptable carrier.
 164. Amethod of inhibiting tumor growth in a mammal, said method comprisingorally administering a therapeutically effective amount of apharmaceutical composition comprising the taxane of claim 96 and atleast one pharmaceutically acceptable carrier.